Substituted polycyclic carbamolypyridone derivative

ABSTRACT

This invention provides compounds having antiviral activities especially inhibiting activity for influenza virus, more preferably provides substituted 3-hydroxy-4-pyridone derivatives having cap-dependent endonuclease inhibitory activity.

TECHNICAL FIELD

This invention relates to substituted polycyclic carbamoylpyridonederivatives having cap-dependent endonuclease inhibitory activity, andpharmaceutical compositions including thereof.

BACKGROUND ART

Influenza is an acute respiratory infectious disease caused by infectionwith an influenza virus. In Japan, there is a report of a few millionsof influenza-like patients every winter, and influenza is accompaniedwith high morbidity and mortality. Influenza is a particularly importantdisease in a high risk population such as baby and elderly, acomplication rate with pneumonia is high in elderly, and death withinfluenza is occupied with elderly in many cases.

As anti-influenza drugs, Symmetrel (trade name: Amantadine) andFlumadine (trade name: Rimantadine) which inhibit the denucleationprocess of a virus, and Oseltamivir (trade name: Tamiflu) and Zanamivir(trade name: Relenza) which are neuraminidase inhibitors suppressingvirus budding and release from a cell are known. However, since problemsof appearances of resistant strains and side effects, and worldwideepidemic of a new-type influenza virus having high pathogenicity andmortality are feared, development of an anti-influenza drug having anovel mechanism has been desired.

Since a cap-dependent endonuclease which is an influenza virus-derivedenzyme is essential for virus proliferation, and has the virus-specificenzymatic activity which is not possessed by a host, it is believed thatthe endonuclease is suitable for a target of an anti-influenza drug. Thecap-dependent endonuclease has a host mRNA precursor as a substrate, andhas the endonuclease activity of producing a fragment of 9 to 13 basesincluding a cap structure (not including the number of bases of the capstructure). This fragment functions as a primer of a virus RNApolymerase, and is used in synthesizing mRNA encoding a virus protein.That is, it is believed that a substance which inhibits thecap-dependent endonuclease inhibits synthesis of a virus protein byinhibiting synthesis of virus mRNA and, as a result, inhibits virusproliferation.

As the substance which inhibits the cap-dependent endo nuclease,flutamide (Patent Document 1 and Non-Patent Documents 1 and 2) and4-substituted 2,4-dioxobutanoic acid (Non-Patent Documents 3 to 5) arereported, but they have not yet led to clinical use as anti-influenzadrugs. In addition, Patent Documents 2 to 9 and Non-Patent Document 6describe compounds having a similar structure to that of this invention,however, the documents do not describe cap-dependent endonuclease.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent Document 1] GB No. 2280435 specification-   [Patent Document 2] International Publication No. 2007/049675    pamphlet-   [Patent Document 3] International Publication No. 2006/088173    pamphlet-   [Patent Document 4] International Publication No. 2006/066414    pamphlet-   [Patent Document 5] International Publication No. 2005/092099    pamphlet-   [Patent Document 6] International Publication No. 2005/087766    pamphlet-   [Patent Document 7] International Publication No. 2005/016927    pamphlet-   [Patent Document 8] International Publication No. 2004/024078    pamphlet-   [Patent Document 9] International Publication No. 2006/116764    pamphlet

Non-Patent Documents

-   [Non-Patent Document 1] Tetrahedron Lett 1995, 36(12), 2005-   [Non-Patent Document 2] Tetrahedron Lett 1995, 36(12), 2009-   [Non-Patent Document 3] Antimicrobial Agents And Chemotherapy,    December 1994, p. 2827-2837-   [Non-Patent Document 4] Antimicrobial Agents And Chemotherapy, May    1996, p. 1304-1307-   [Non-Patent Document 5] J. Med. Chem. 2003, 46, 1153-1164-   [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letters    17(2007)5595-5599

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide compounds havingantiviral activities especially inhibiting growth activity of influenzavirus. More preferably, this invention provides compounds and medicamentcontaining the same which inhibit increase of influenza virus byexhibiting cap-dependent endonuclease inhibitory activity.

Means for Solving the Problems Item 1′

A CAP dependent endonuclease inhibitor containing a compound representedby formula (I), a pharmaceutically acceptable salt, or a solvatethereof:

(wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(X1))(R^(X2)),—Z—N(R^(X3))—SO₂—(R^(X4)),—Z—C(═O)—N(R^(X5))—SO₂—(R^(X6)),—Z—N(R^(X7))—C(═O)—R^(X8),—Z—C(═O)—N(R^(X9))(R^(X10)),

—Z—S—R^(X11),

—Z—SO₂—R^(X12),

—Z—S(═O)—R^(X13),

—Z—N(R^(X14))—C(═O)—O—R^(X15),—Z—N(R^(X16))—C(═O)—N(R^(X17))(R^(X18)),—Z—C(═O)—N(R^(X19))—C(═O)—N(R^(X20))(R^(X21)), or—Z—N(R^(X22))—C(═O)—C(═O)—R^(X23)(wherein R^(X1), R^(X2), R^(X3), R^(X5), R^(X7), R^(X8), R^(X9),R^(X10), R^(X11), R^(X14), R^(X15), R^(X16), R^(X17), R^(X18), R^(X19),R^(X20), R^(X21), R^(X22), and R^(X23) are each independently selectedfrom a substituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A, R^(X4), R^(X6), R^(X12), and R^(X13) are eachindependently selected from a substituent group consisting of, loweralkyl optionally substituted by substituent group A, lower alkenyloptionally substituted by substituent group A, lower alkynyl optionallysubstituted by substituent group A, carbocyclic group optionallysubstituted by substituent group A, heterocyclic group optionallysubstituted by substituent group A, carbocycle lower alkyl optionallysubstituted by substituent group A, and heterocycle lower alkyloptionally substituted by substituent group A,R^(X1) and R^(X2), R^(X9) and R^(X10), R^(X17) and R^(X18), and R^(X20)and R^(X21) each may be taken together with an adjacent atom to formheterocycle, andZ is a bond or straight or branched lower alkylene);R² is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(Y1))—SO₂—RY²,—Z—N(R^(Y3))—C(═O)—R^(Y4),—Z—N(R^(Y5))—C(═O)—O—R^(Y6),—Z—C(═O)—N(R^(Y7))(R^(Y8)),—Z—N(R^(Y9))(R^(Y10)), or—Z—SO₂—R^(Y11)(wherein R^(Y1), R^(Y3), R^(Y4), R^(Y5), R^(Y6), R^(Y7), R^(Y8), R^(Y9),and R^(Y10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group A, lower alkenyl optionally substituted by substituentgroup A, lower alkynyl optionally substituted by substituent group A,carbocyclic group optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,and heterocycle lower alkyl optionally substituted by substituent groupA, R^(Y2) and R^(Y11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(Y7) and R^(Y8), and R^(Y9) and R^(Y10) may be taken together with anadjacent atom to form heterocycle andZ is a bond or straight or branched lower alkylene);R³ is hydrogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocycleoxy lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocycleoxy lower alkyl optionally substituted by substituentgroup A, heterocyclecarbonyl optionally substituted by substituent groupA, heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(Z1))—SO₂—R^(Z2),—Z—N(R^(Z3))—C(═O)—R^(Z4),—Z—N(R^(Z5))—C(═O)—O—R^(Z6),—Z—C(═O)—N(R^(Z7))(R^(Z8)),—Z—N(R^(Z9))(R^(Z10)),—Z—SO₂—R^(Z11), or—Z—N(R^(Z12))—O—C(═O)—R^(Z13)(wherein R^(Z1), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7), R^(Z8), R^(Z9),R^(Z10), R^(Z12), and R^(Z13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A,R^(Z2) and R^(Z11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(Z7) and R^(Z8), and R^(Z9) and R^(Z10) each may be taken togetherwith an adjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene) and;a) either A¹ or A² is CR⁵R⁶, and the other is NR⁷, orb) A¹ is CR⁸R⁹, and A² is CR¹⁰R¹¹,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from asubstituent group consisting of hydrogen, carboxy, cyano, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyl carbonyl optionally substituted bysubstituent group A, lower alkyl oxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocycleoxy lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, heterocycle lower alkyl optionally substituted bysubstituent group A, heterocycleoxy lower alkyl optionally substitutedby substituent group A, heterocyclecarbonyl optionally substituted bysubstituent group A, heterocycleoxycarbonyl optionally substituted bysubstituent group A,

—Z—S—R^(V1), —Z—S(═O)—R^(V2),

—Z—SO₂—R^(V3),

—C(═O) C(═O)—R^(V4),

—C(═O)—N(R^(V5))(R^(V6))—Z—N(R^(V7))—C(═O)—O—R^(V8), or—Z—N(R^(V9))—C(═O)—R^(V10)(wherein R^(V1), R^(V4), R^(V5), R^(V6), R^(V7), R^(V8), R^(V9), andR^(V10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group A, lower alkenyl optionally substituted by substituentgroup A, lower alkynyl optionally substituted by substituent group A,carbocyclic group optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,and heterocycle lower alkyl optionally substituted by substituent groupA,R^(V2) and R^(V3) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(V5) and R^(V6) may be taken together with an adjacent atom to formheterocycle, andZ is a bond or straight or branched lower alkylene), andR⁵ and R⁶ may be taken together with an adjacent atom to formcarbocycle;1) when A¹ is CR⁵R⁶ and A² is NR⁷,R³ and R⁷ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may form acondensed ring,2) when A¹ is NR⁷ and A² is CR¹⁰R¹¹,R³ and R⁶ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may formcondensed ring,or3) when A¹ is CR⁸R⁹, and A² is CR¹⁰R¹¹,R⁸ and R¹⁰ may be taken together with an adjacent atom to form a bond,and R⁸ and R¹⁰ may be taken together with an adjacent atom to formcarbocycle or heterocycle, orR³ and R¹¹ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may formcondensed ring;with a proviso that the following case of c) and d) are excluded;c) R⁵, R⁶, and R⁷ are all hydrogensd) R⁸, R⁹, R¹⁰, and R¹¹ are all hydrogens;Substituent group A: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, loweralkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group,heterocyclic group substituted by oxo, carbocycle lower alkyloxy,carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl,heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocyclelower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, halogeno lower alkyl carbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and loweralkylsulfonylamino;Substituent group B: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno loweralkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy,lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, loweralkylsulfonylamino, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A).

Item 2′

A CAP dependent endonuclease inhibitor according to item 1′, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(X1))(R^(X2))—Z—N(R^(X3))—SO₂—(R^(X4)),—Z—C(═O)—N(R^(X5))—SO₂—(R^(X6)),—Z—N(R^(X7))—C(═O)—R^(X8),

—Z—S—R^(X11),

—Z—SO₂—R^(X12),

—Z—S(═O)—R^(X13),

—Z—N(R^(X14))—C(═O)—O—R^(X8),—Z—N(R^(X16))—C(═O)—N(R^(X17))(R^(X18)), or—Z—N(R^(X22))—C(═O)—C(═O)—R^(X23)(Substituent group A, R^(X1), R^(X2), R^(X3), R^(X4), R^(X5), R^(X6),R^(X7), R^(X8), R^(X11), R^(X12), R^(X13), R^(X14), R^(X15), R^(X16),R^(X17), R^(X18), R^(X22), R^(X23), and Z are same meaning as those ofitem 1′).

Item 3′

A CAP dependent endonuclease inhibitor according to item 1′, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A,—Z—N(R^(X1))(R^(X2)),—Z—N(R^(X7))—C(═O)—R^(X8), or—Z—N(R^(X14))—C(═O)—O—R^(X15)(Substituent group A, R^(X1), R^(X2), R^(X7), R^(X8), R^(X14), R^(X15),and Z are same meaning as those of item 1′).

Item 4′

A CAP dependent endonuclease inhibitor according to item 1′, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkyl carbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, or—Z—N(R^(X1))(R^(X2))(Substituent group A, R^(X1), R^(X2), and Z are same meaning as those ofitem 1′).

Item 5′

A CAP dependent endonuclease inhibitor according to item 1′, wherein R¹is hydrogen or carboxy.

Item 6′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 5′, wherein

R² is hydrogen, lower alkyl optionally substituted by substituent groupA, carbocycle lower alkyl optionally substituted by substituent group A,heterocycle lower alkyl optionally substituted by substituent group A,or—Z—N(R^(Y9))(R^(Y10))(Substituent group A, R^(Y9), R^(Y10), and Z are same meaning as thoseof item 1′).

Item 7′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 5′, wherein

R² is hydrogen or lower alkyl optionally substituted by substituentgroup A(Substituent group A is same meaning as that of item 1′).

Item 8′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 7′, wherein

R³ is hydrogen, lower alkyl optionally substituted by substituent groupA, lower alkenyl optionally substituted by substituent group A, loweralkynyl optionally substituted by substituent group A, carbocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, carbocycleoxy lower alkyloptionally substituted by substituent group A, heterocycle lower alkyloptionally substituted by substituent group A,—Z—N(R^(Z1))—SO₂—R^(Z2),—Z—N(R^(Z3))—C(═O)—R^(Z4),—Z—N(R^(Z5))—C(═O)O—R^(Z6),—Z—C(═O)—N(R^(Z7))(R^(Z8)), or—Z—N(R^(Z9))(R^(Z10))(Substituent group A, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6),R^(Z7), R^(Z8), R^(Z9), R^(Z10), and Z are same meaning as those of item1′)

Item 9′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 8′, wherein

A¹ is CR⁸R⁹, A² is CR¹⁰R¹¹,R⁹, R¹⁰, and R¹¹ are hydrogen or lower alkyl optionally substituted bysubstituent group A, andR⁸ is lower alkyl optionally substituted by substituent group A,carbocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,carbocycleoxy lower alkyl optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,heterocycle lower alkyl optionally substituted by substituent group A,heterocycleoxy lower alkyl optionally substituted by substituent groupA,

—Z—S—R^(V1), —Z—S(═O)—R^(V2), or

—Z—SO₂—R^(V3)(Substituent group A, R^(V1), R^(V2), R^(V3), and Z are same meaning asthose of item 1′).

Item 10′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 8′, wherein

A is CR⁸R⁹, A² is CR¹⁰R¹¹,R⁸, R⁹, and R¹¹ are hydrogen, or lower alkyl optionally substituted bysubstituent group A, andR¹⁰ is lower alkyl optionally substituted by substituent group A,carbocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,carbocycleoxy lower alkyl optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,heterocycle lower alkyl optionally substituted by substituent group A,heterocycleoxy lower alkyl optionally substituted by substituent groupA,

—Z—S—R^(V1), —Z—S(═O)—R^(V2), or

—Z—SO₂—R^(V3)(Substituent group A, R^(V1), R^(V2), R^(V3), and Z are same meaning asthose of item 1′).

Item 11′

A CAP dependent endonuclease inhibitor according to any one of items 1′to 8′, wherein

A¹ is CR⁸R⁹, A² is CR¹⁰R¹¹,R⁹ and R¹¹ are hydrogen,i) either R⁸ or R¹⁰ is a group shown below:

(wherein R^(E6) is selected from substituent group A, m is an integer of0 or more, and substituent group A is same meaning as those of item 1′)and;ii) the other of R⁸ or R¹⁰ is hydrogen, or lower alkyl optionallysubstituted by substituent group A;

Item 12′

CAP dependent endonuclease inhibitor according to item 11′, wherein

A¹ is CR⁸R⁹, A² is CR¹⁰R¹¹,R⁹ and R¹¹ are hydrogen,i) either R⁸ or R¹⁰ is a group shown below:

(wherein R^(E6) is selected from substituent group A,m is an integer of 0 or more, substituent group A is same meaning asthat of item 1′)and;ii) the other of R⁸ or R¹⁰ is hydrogen or lower alkyl optionallysubstituted by substituent group A.

Item 13′

A compound represented by formula (II), or a pharmaceutically acceptablesalt thereof or a solvate thereof:

(whereinR^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A3))—SO₂—(R^(A4)),—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R^(A11),

—Z—N(R^(A12))—C(═O)—O—R^(A13),—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(wherein R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8), R^(A9),R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17), R^(A18), R^(A19),R^(A20), and R^(A21) are each independently selected from substituentgroup consisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(A4), R^(A6), R^(A1), and R^(A11) are each independently selected fromsubstituent group consisting of, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(A1) and R^(A2), R^(A15) and R^(A16), and R^(A18) and R^(A19) each maybe taken together with an adjacent atom to form heterocyce, and Z is abond or straight or branched lower alkylene);R^(2a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(B1))—SO₂—R^(B2),—Z—N(R^(B3))—C(═O)—R^(B4),—Z—N(R^(B5))—C(═O)—O—R^(B6),—Z—C(═O)—N(R^(B7))(R^(B8)),—Z—N(R^(B9))(R^(B10)), or—Z—SO₂—R^(B11)(wherein R^(B1), R^(B3), R^(B4), R^(B5), R^(B6), R^(B7), R^(B8), R^(B9),and R^(B10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(B2) and R^(B11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(B7) and R^(B8), and R^(B9) and R^(B10) each may be taken togetherwith an adjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene);R^(3a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(C1))—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8)),—Z—N(R^(C9))(R^(C10)),—Z—SO₂—R^(C11), or—Z—N(R^(C12))—O—C(═O)—R^(C13)(wherein R^(C1), R^(C3), R^(C4), R^(C5), R^(C6), R^(C7), R^(C8), R^(C9),R^(C10), R^(C12) and, R^(C13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,R^(C2), and R^(C11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(C7) and R^(C8), and R^(C9) and R^(C10) each may be taken togetherwith an adjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene) and;a) either B¹ or B² is CR^(5a)R^(6a), and the other is NR^(7a),orb) B¹ is CR^(8a)R^(9a) and B² is CR^(10a)R^(11a),R^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a) and R^(11a) are eachindependently selected from a substituent group consisting of hydrogen,carboxy, cyano, lower alkyl optionally substituted by substituent groupC, lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, carbocycle loweralkyl optionally substituted by substituent group C, carbocycleoxy loweralkyl optionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1), —Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),—Z—C(R^(D7))(R^(D8))(R^(D9)),—Z—CH₂—R^(D10),—Z—N(R^(D11))—C(═O)—O—R^(D12), or—Z—N(R^(D13))—C(═O)—R^(D14)(wherein R^(D1), R^(D4), R^(D5), R^(D6), R^(D9), R^(D11), R^(D12),R^(D13), and R^(D14) are each independently selected from a substituentgroup consisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(D2) and R^(D3) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(D7), R^(D8), and R^(D10) are each independently selected from asubstituent group consisting of carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C,R^(D5) and R^(D6) may be taken together with an adjacent atom to formheterocycle,Y is straight or branched lower alkylene, andZ is a bond or straight or branched lower alkylene);R^(D5) and R^(D6) may be taken together with an adjacent atom to formcarbocycle;1) when B¹ is CR^(5a)R^(6a) and B² is NR^(7a),R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D,2) when B¹ is NR^(7a) and B² is CR^(5a)R^(6a),R^(3a) and R^(6a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, or3) when B¹ is CR^(8a)R^(9a) and B² is CR^(10a)R^(11a),R^(8a) and R^(10a) may be taken together with an adjacent atom to formcarbocycle or heterocycle optionally substituted by substituent group D,orR^(3a) and R^(11a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D,whereinwhen B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a), and R^(9a) ishydrogen, and R^(11a) is hydrogen,i) either R^(8a) or R^(10a) is—Z—C(R^(E1))(R^(E2))(R^(E3))

—Y—S—R^(E4),

—Z—CH₂—R^(E5), ora group shown below:

(wherein R^(E1) and R^(E2) are each independently, carbocycle optionallysubstituted by substituent group C, and heterocycle optionallysubstituted by substituent group C,R^(E3) is selected from a substituent group consisting of hydrogen,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C,R^(E4) is selected from a substituent group consisting of carbocyclelower alkyl optionally substituted by substituent group C, andheterocycle lower alkyl optionally substituted by substituent group C,R^(E5) is aromatic heterocycle optionally substituted by substituentgroup C,R^(E6) is selected from a substituent group C,m is an integer of 0 or more,provided thatm of R^(E6)s is same or different groups selected from substituent groupCY is straight or branched lower alkylene, andZ is a bond or straight or branched lower alkylene); andii) the other of R^(8a) or R^(10a) ishydrogen, carboxy, cyano, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Y—S—R^(F1), —C(═O)—C(═O)—R^(F2), or

—C(═O)—N(R^(F3))(R^(F4))(wherein R^(F1), R^(F2), R^(F3), and R^(F4) are each independently,hydrogen, lower alkyl optionally substituted by substituent group C,lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C, and Y is straightor branched lower alkylene);with a proviso that the following c) and d) are excludedc) R^(5a), R^(6a), and R^(7a) are all hydrogensd) R^(8a), R^(9a), R^(10a), and R^(11a) are all hydrogens;Substituent group C: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, loweralkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group,heterocyclic group substituted by oxo, carbocycle lower alkyloxy,carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl,heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocyclelower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, halogeno lower alkyl carbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and loweralkylsulfonylamino;Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno loweralkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy,lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, loweralkylsulfonylamino, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C).

Item 14′

The compound according to item 13′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A3))—SO₂—(R^(A4)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),—Z—N(R^(A12))—C(═O)—O—R^(A13), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(substituent group C, R^(A1), R^(A2), R^(A3), R^(A4), R^(A7), R^(A8),R^(A9), R^(A10), R^(A12), R^(A13), R^(A20), R^(A21), and Z are samemeaning as those of item 13).

Item 15′

The compound according to item 13′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A7))—C(═O)—R^(A8), or—Z—N(R^(A12))—C(═O)—O—R^(A13)(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),and Z are same as those of item 13′).

Item 16′

The compound according to item 13′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, or—Z—N(R^(A1))(R^(A2))(substituent group C, R^(A1), R^(A2), and Z are same as those of item13′).

Item 17′

The compound according to item 13′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, or carboxy.

Item 18′

The compound according to any one of items 13′ to 17′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, or—Z—N(R^(B9))(R^(B10))(substituent group C, R^(B9), R^(B10), and Z are same as those of item13′).

Item 19′

The compound according to any one of items 13′ to 17′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen or lower alkyl optionally substituted bysubstituent group C(substituent group C is same as that of item 13′).

Item 20′

The compound according to any one of items 13′ to 19′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(3a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,—Z—N(R^(C1))—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8)), or—Z—N(R^(C9))(R^(C10))(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), RC¹⁰, and Z are same as those of item 13′).

Item 21′

The compound according to any one of items 13′ to 19′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(3a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C,(substituent group C, is same as that of item 13′).

Item 22′

The compound according to any one of items 13′ to 21′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a), andR^(5a), R^(6a) and R^(7a) are each independently hydrogen, carboxy,cyano, lower alkyl optionally substituted by substituent group C, loweralkenyl optionally substituted by substituent group C, lower alkynyloptionally substituted by substituent group C, lower alkyl carbonyloptionally substituted by substituent group C, lower alkyl oxycarbonyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1), —Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),—Z—C(R^(D7))(R^(D8))(R^(D9))—Z—N(R^(D11))—C(═O)—O—R^(D12), or—Z—N(R^(D13))—C(═O)—R^(D14)(substituent group C, R^(D1), R^(D2), R^(D3), R^(D4), R^(D5), R^(D6),R^(D7), R^(D8), R^(D9), R^(D11), R^(D12), R^(D13), R^(D14), Y and Z aresame as those of item 13).

Item 23′

The compound according to any one of items 13′ to 21′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a),R^(5a) is hydrogen,R^(6a) is hydrogen, or lower alkyl optionally substituted by substituentgroup C, andR^(7a) is lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or—Z—C(R^(D7))(R^(D8))(R^(D9))(substituent group C, R^(D7), R^(D8), R^(D9) and Z are same as item 13′

Item 24′

The compound according to any one of items 13′ to 21′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(5a)R^(6a), and B² is NR^(7a),R^(5a) is hydrogen,R^(6a) is hydrogen, or lower alkyl optionally substituted by substituentgroup C, andR^(7a) is lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or—Z—C(R^(D7))(R^(D8))(R^(D9))(Substituent group C, R^(D7), R^(D8), R^(D9), and Z are same as item13′).

Item 25′

The compound according to items 23′ or 24′, or the pharmaceuticallyacceptable salt thereof or the solvate thereof,

wherein R^(7a) is a group shown below:

(wherein R^(E6) and m are same as those of item 13′).

Item 26′

The compound according to items 13′ or 21′, or the pharmaceuticallyacceptable salt thereof or the solvate thereof,

whereinB¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, and R^(11a) is hydrogen, andi) either R^(8a) or R^(10a) is a group shown below:

(wherein R^(E6), and m are same as those of item 13′); andii) the other of R^(8a) or R^(10a) ishydrogen, or lower alkyl optionally substituted by substituent group C,(Substituent group C is same as those of item 13′).

Item 27′

The compound according to any one of items 13′ to 19′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(5a)R^(6a), and B² is NR^(7a),R^(6a) is hydrogen,R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(5a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1), —C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(R^(D4))(wherein R^(D1), R^(D2), R^(D3), R^(D4), Y, substituent group C andsubstituent group D are the same as item 13′).

Item 28′

The compound according to item 27′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(5a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C(wherein Substituent group C is same as item 13′).

Item 29′

The compound according to any one of items 13′ to 19′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, and R^(10a) is hydrogen,R^(3a) and R^(11a) are taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(8a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1), —C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(R^(D4))(wherein R^(D1), R^(D2), R^(D3), R^(D4), Y, substituent group C andsubstituent group D is same as item 13′).

Item 30′

The compound according to item 29′, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(8a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C(wherein substituent group C is same as that of item 13′).

Item 31′

The compound according to any one of items 27′ to 30′, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein substituent group D is carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C(wherein substituent group C is same as that of item 13′).

Item 32′

A pharmaceutical composition containing a compound according to any oneof items 13′ to 31′, or a pharmaceutically acceptable salt thereof or asolvate thereof.

Item 33′

The pharmaceutical composition according to item 32′ which exhibits antiinfluenza activity.

Item 34′

The compound according to any one of items 13′ to 31′ for treatingand/or preventing influenza infectious disease.

Item 35′

The compound according to any one of items 13′ to 31′, or thepharmaceutically acceptable salt thereof or the solvate thereof, fortreating and/or preventing influenza infectious disease.

Item 36′

The pharmaceutical composition according to item 32′ which exhibits CAPdependent endonuclease inhibitory activity.

This invention provides following items as another aspect.

Item 1

A CAP dependent endonuclease inhibitor containing a compound representedby formula (I), a pharmaceutically acceptable salt, or a solvatethereof:

(whereinR¹ is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(X1))(R^(X2)),—Z—N(R^(X3))—SO₂—(R^(X4)),—Z—C(═O)—N(R^(X5))—SO₂—(R^(X6)),—Z—N(R^(X7))—C(═O)—R^(X8),—Z—C(═O)—N(R^(X9))(R^(X10)),

—Z—S—R^(X11),

—Z—SO₂—R^(X12),

—Z—S(═O)—R^(X13),

—Z—N(R^(X14))—C(═O)—O—R^(X15),—Z—N(R^(X16))—C(═O)—N(R^(X17))(R^(X18))—Z—C(═O)—N(R^(X19))—C(═O)—N(R^(X20))(R^(X21)), or—Z—N(R^(X22))—C(═O)—C(═O)—R^(X23)(wherein R^(X1), R^(X2), R^(X3), R^(X5), R^(X7), R^(X8), R^(X9),R^(X10), R^(X11), R^(X14), R^(X15), R^(X16), R^(X17), R^(X18), R^(X19),R^(X20), R^(X21), R^(X22) and R²³ are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A, R^(X4), R^(X6), R^(X12), and R^(X13) are eachindependently selected from a substituent group consisting of, loweralkyl optionally substituted by substituent group A, lower alkenyloptionally substituted by substituent group A, lower alkynyl optionallysubstituted by substituent group A, carbocyclic group optionallysubstituted by substituent group A, heterocyclic group optionallysubstituted by substituent group A, carbocycle lower alkyl optionallysubstituted by substituent group A, and heterocycle lower alkyloptionally substituted by substituent group A,R^(X1) and R^(X2), R^(X9) and R^(X10), R^(X17) and R^(X18), and R^(X20)and R^(X21) each may be taken together with an adjacent atom to formheterocycle, andZ is a bond or straight or branched lower alkylene);R² is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(Y1))—SO₂—R^(Y2),—Z—N(R^(Y3))—C(═O)—R^(Y4),—Z—N(R^(Y5))—C(═O)—O—R^(Y6),—Z—C(═O)—N(R^(Y7))(R^(Y8))—Z—N(R^(Y9))(R^(Y10)), or—Z—SO₂—R^(Y11)(wherein R^(Y1), R^(Y3), R^(Y4), R^(Y5), R^(Y6), R^(Y7), R^(Y8), R^(Y9),and R^(Y10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group A, lower alkenyl optionally substituted by substituentgroup A, lower alkynyl optionally substituted by substituent group A,carbocyclic group optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,and heterocycle lower alkyl optionally substituted by substituent groupA,R^(Y2) and R^(Y1) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(Y7) and R^(Y8), and R^(Y9) and R^(Y10) each may be taken togetherwith an adjacent atom to form heterocycle andZ is a bond or straight or branched lower alkylene);R³ is hydrogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocycleoxy lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocycleoxy lower alkyl optionally substituted by substituentgroup A, heterocyclecarbonyl optionally substituted by substituent groupA, heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(Z1))—SO₂—R^(Z2),—Z—N(R^(Z3))—C(═O)—R^(Z4),—Z—N(R^(Z5))—C(═O)—O—R^(Z6),—Z—C(═O)—N(R^(Z7))(R^(Z8)),—Z—N(R^(Z9))(R^(Z10))—Z—SO₂—R^(Z11), or—Z—N(R^(Z12))—O—C(═O)—R^(Z13)(wherein R^(Z1), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7), R^(Z8), R^(Z9),R^(Z10), R^(Z12), and R^(Z13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkynyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A,R^(Z2) and R^(Z11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(Z7) and R^(Z8), and R^(Z9) and R^(Z10) each may be taken togetherwith an adjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene) and;a) either A¹ or A² is CR⁵R⁶, and the other is NR⁷, or A¹ is CR⁸R⁹, andA² is CR¹⁰R¹¹,b) R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected froma substituent group consisting of hydrogen, carboxy, cyano, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyl carbonyl optionally substituted bysubstituent group A, lower alkyl oxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocycleoxy lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, heterocycle lower alkyl optionally substituted bysubstituent group A, heterocycleoxy lower alkyl optionally substitutedby substituent group A, heterocyclecarbonyl optionally substituted bysubstituent group A, heterocycleoxycarbonyl optionally substituted bysubstituent group A,

—Z—S—R^(V1), —Z—S(═O)—R^(V2),

—Z—SO₂—R^(V3),

—C(═O)—C(═O)—R^(V4), or

—C(═O)—N(R^(V5))(R^(V6)),

(wherein R^(V1), R^(V4), R^(V5), and R^(V6) are each independentlyselected from a substituent group consisting of hydrogen, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, carbocyclic group optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, and heterocycle lower alkyl optionally substitutedby substituent group A,

R^(V2) and R^(V3) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup A, lower alkenyl optionally substituted by substituent group A,lower alkynyl optionally substituted by substituent group A, carbocyclicgroup optionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A,R^(V5) and R^(V6) may be taken together with an adjacent atom to formheterocycle, andZ is a bond or straight or branched lower alkylene);1) when A¹ is CR⁵R⁶ and A² is NR⁷,R³ and R⁷ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may formcondensed ring,2) when A¹ is NR⁷ and A² is CR⁵R⁶,R³ and R⁶ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may formcondensed ring,or3) when A¹ is CR⁸R⁹ and A² is CR¹⁰R¹¹,R⁸ and R¹⁰ may be taken together with an adjacent atom to form a bond,and R⁸ and R¹⁰ may be taken together with an adjacent atom to formcarbocycle or heterocycle, orR³ and R¹¹ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B or may formcondensed ring;Substituent group A: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocyclic group, heterocyclic group, carbocycle lower alkyloxy,heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;Substituent group B: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocyclic group, heterocyclic group, carbocycle lower alkyloxy,heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino,carbocyclic group optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,carbocycle lower alkyl optionally substituted by substituent group A,and heterocycle lower alkyl optionally substituted by substituent groupA).

Item 2

A CAP dependent endonuclease inhibitor according to item 1, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group A, lower alkenyl optionallysubstituted by substituent group A, lower alkynyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkenyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, carbocyclic group optionally substituted bysubstituent group A, carbocycle lower alkyl optionally substituted bysubstituent group A, carbocyclecarbonyl optionally substituted bysubstituent group A, carbocycleoxy optionally substituted by substituentgroup A, carbocycleoxycarbonyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA, heterocyclecarbonyl optionally substituted by substituent group A,heterocycleoxy optionally substituted by substituent group A,heterocycleoxycarbonyl optionally substituted by substituent group A,—Z—N(R^(X1))(R^(X2)),—Z—N(R^(X3))—SO₂—(R^(X4)),—Z—C(═O)—N(R^(X5))—SO₂—(R^(X6)),—Z—N(R^(X7))—C(═O)—R^(X8),

—Z—S—R^(X11),

—Z—SO₂—R^(X12),

—Z—S(═O)—R^(X13),

—Z—N(R^(X14))—C(═O)—O—R^(X15),—Z—N(R^(X16))—C(O)—N(R^(X17))(R^(X18)), or—Z—N(R^(X22))—C(═O)—C(═O)—R^(X23)(Substituent group A, R^(X1), R^(X2), R^(X3), R^(X4), R^(X5), R^(X6),R^(X7), R^(X8), R^(X11), R^(X12), R^(X13), R^(X14), R^(X15), R^(X16),R^(X17), R^(X18), R^(X22), R^(X23), andZ are same meaning as those of item 1).

Item 3

A CAP dependent endonuclease inhibitor according to item 1, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkylcarbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A,—Z—N(R^(X1))(R^(X2)),—Z—N(R⁷)—C(═O)—R^(X8), or—Z—N(R^(X14))—C(═O)—O—R^(X15)(Substituent group A, R^(X1), R^(X2), R^(X7), R^(X8), R^(X14), R^(X15),and Z are same meaning as those of item 1).

Item 4

A CAP dependent endonuclease inhibitor according to item 1, wherein

R¹ is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionallysubstituted by substituent group A, lower alkenyl optionally substitutedby substituent group A, lower alkyloxy optionally substituted bysubstituent group A, lower alkyl carbonyl optionally substituted bysubstituent group A, lower alkyloxycarbonyl optionally substituted bysubstituent group A, heterocyclic group optionally substituted bysubstituent group A, or—Z—N(R^(X1))(R^(X2))(Substituent group A, R^(X1), R^(X2), and Z are same meaning as those ofitem 1).

Item 5

A CAP dependent endonuclease inhibitor according to item 1, wherein R¹is hydrogen or carboxy.

Item 6

A CAP dependent endonuclease inhibitor according to any one of items 1to 5, wherein

R² is hydrogen, lower alkyl optionally substituted by substituent groupA, carbocycle lower alkyl optionally substituted by substituent group A,heterocycle lower alkyl optionally substituted by substituent group A,or—Z—N(R^(Y9))(R^(Y10))(Substituent group A, R^(Y9), R^(Y10), and Z are same meaning as thoseof item 1).

Item 7

A CAP dependent endonuclease inhibitor according to any one of items 1to 5, wherein

R² is hydrogen or lower alkyl optionally substituted by substituentgroup A, heterocycle lower alkyl optionally substituted by substituentgroup A,(Substituent group A is same meaning as that of item 1).

Item 8

A CAP dependent endonuclease inhibitor according to any one of items 1to 7, wherein

R³ is hydrogen, lower alkyl optionally substituted by substituent groupA, lower alkenyl optionally substituted by substituent group A, loweralkynyl optionally substituted by substituent group A, carbocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, carbocycleoxy lower alkyloptionally substituted by substituent group A,—Z—N(R^(Z1))—SO₂—R^(Z2),—Z—N(R^(Z3))—C(═O)—R^(Z4),—Z—N(R^(Z5))—C(═O)—O—R^(Z6),—Z—C(═O)—N(R^(Z7))(R^(Z8)), or—Z—N(R^(Z9))(R^(Z10))(Substituent group A, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6),R^(Z7), R^(Z8), R^(Z9), R^(Z10), and Z are same meaning as those of item1).

Item 9

A CAP dependent endonuclease inhibitor according to any one of items 1to 8, wherein

A¹ is NR⁷,A² is CHR⁶, andR⁶ and R⁷ are each independently hydrogen, lower alkyl optionallysubstituted by substituent group A, carbocyclic group optionallysubstituted by substituent group A, carbocycle lower alkyl optionallysubstituted by substituent group A, carbocycleoxy lower alkyl optionallysubstituted by substituent group A, heterocyclic group optionallysubstituted by substituent group A, heterocycle lower alkyl optionallysubstituted by substituent group A, heterocycleoxy lower alkyloptionally substituted by substituent group A,

—Z—S—R^(V1), —Z—S(═O)—R^(V2) or

—Z—SO₂—R^(V3)(Substituent group A, R^(V1), R^(V2), R^(V3), and Z are same meaning asthose of item 1).

Item 10

A CAP dependent endonuclease inhibitor according to any one of items 1to 8, wherein

A¹ is CHR⁹,A² is CHR¹¹, andR⁹ and R¹¹ are each independently hydrogen, lower alkyl optionallysubstituted by substituent group A, carbocyclic group optionallysubstituted by substituent group A, carbocycle lower alkyl optionallysubstituted by substituent group A, carbocycleoxy lower alkyl optionallysubstituted by substituent group A, heterocyclic group optionallysubstituted by substituent group A, heterocycle lower alkyl optionallysubstituted by substituent group A, heterocycleoxy lower alkyloptionally substituted by substituent group A,

—Z—S—R^(V1), —Z—S(═O)—R^(V2), or

—Z—SO₂—R^(V3)(Substituent group A, R^(V1), R^(V2), R^(V3), and Z are same meaning asthose of item 1).

Item 11

A CAP dependent endonuclease inhibitor according to any one of items 1to 7, wherein

A¹ is CHR⁹,A² is CHR¹¹,R³ and R¹¹ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B, and R⁹ ishydrogen, carbocyclic group optionally substituted by substituent groupA, carbocycle lower alkyl optionally substituted by substituent group A,heterocyclic group optionally substituted by substituent group A,heterocycle lower alkyl optionally substituted by substituent group A,(Substituent group A and substituent group B are same meaning as thoseof item 1).

Item 12

A CAP dependent endonuclease inhibitor according to any one of items 1to 7, wherein

A¹ is CHR⁶,

A2 is NR⁷,

R³ and R⁷ may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group B,R⁶ is hydrogen, carbocyclic group optionally substituted by substituentgroup A, carbocycle lower alkyl optionally substituted by substituentgroup A, heterocyclic group optionally substituted by substituent groupA, heterocycle lower alkyl optionally substituted by substituent groupA,(Substituent group A and substituent group B are same meaning as thoseof item 1).

Item 13

A compound represented by formula (II), or a pharmaceutically acceptablesalt thereof or a solvate thereof:

(whereinR^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A3))—SO₂—(R^(A4)),—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R^(A11),

—Z—N(R^(A12))—C(═O)—O—R^(A13),—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(wherein R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8), R^(A9),R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17), R^(A18), R^(A19),R^(A20), and R^(A21) are each independently selected from substituentgroup consisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(A4), R^(A6), R^(A10), and R^(A11) are each independently selectedfrom substituent group consisting of, lower alkyl optionally substitutedby substituent group C, lower alkenyl optionally substituted bysubstituent group C, lower alkynyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(A1) and R^(A2), R^(A15) and R^(A16), and R^(A18) and R^(A19) may betaken together with an adjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene);R^(2a) is hydrogen, halogen, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,—Z—N(R^(B1))—SO₂—R^(B2),—Z—N(R^(B3))—C(═O)—R^(B4),—Z—N(R^(B5))—C(═O)—O—R^(B6),—Z—C(═O)—N(R^(B7))(R^(B8)),—Z—N(R^(B9))(R^(B10)), or—Z—SO₂—R^(B11)(wherein R^(B1), R^(B3), R^(B4), R^(B5), R^(B6), R^(B7), R^(B8), R^(B9),and R^(B10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,R^(B2) and R^(B11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(B7) and R^(B8), and R^(B9) and R^(B10) may be taken together with anadjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene);R^(3a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(C1))—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8)),—Z—N(R^(C9))(R^(C10)),—Z—SO₂—R^(C11), or—Z—N(R^(C12))—O—C(═O)—R^(C13)(wherein R^(C1), R^(C3), R^(C4), R^(C5), R^(C6), R^(C7), R^(C8), R^(C9),R^(C10), R^(C12) and, R^(C13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,R^(C2) and R^(C11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(C7) and R^(C8), and R^(C9) and R^(C10) may be taken together with anadjacent atom to form heterocycle, andZ is a bond or straight or branched lower alkylene) and;a) either B¹ or B² is CR^(5a)R^(6a), and the other is NR^(7a),orb) B¹ is CR^(8a)R^(9a) and B² is CR^(10a)R^(11a),R^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a) and R^(11a) are eachindependently selected from a substituent group consisting of hydrogen,carboxy, cyano, lower alkyl optionally substituted by substituent groupC, lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, carbocycle loweralkyl optionally substituted by substituent group C, carbocycleoxy loweralkyl optionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1), —Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),—Z—C(R^(D7))(R^(D8))(R^(D9)), or—Z—CH₂—R^(D10),(wherein R^(D1), R^(D4), R^(D5), R^(D6), and R^(D9) are eachindependently selected from a substituent group consisting of hydrogen,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C,R^(D2), and R^(D3) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,R^(D7), R^(D8), and R^(D10) are each independently selected from asubstituent group consisting of carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C,R^(D5) and R^(D6) may be taken together with an adjacent atom to formheterocycle,Y is straight or branched lower alkylene, andZ is a bond or straight or branched lower alkylene);1) when B¹ is CR^(5a)R^(6a) and B² is NR^(7a),R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D,2) when B¹ is NR^(7a) and B² is CR^(5a)R^(6a),R^(3a) and R^(6a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, or3) when B¹ is CR^(8a)R^(9a) and B² is CR^(10a)R^(11a),R^(8a) and R^(10a) may be taken together with an adjacent atom to formcarbocycle or heterocycle optionally substituted by substituent group D,orR^(3a) and R^(11a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D,whereinwhen B is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a), and R^(9a) ishydrogen, and R^(11a) is hydrogen,i) either R^(8a) or R^(10a) is—Z—C(R^(E1))(R^(E2))(R^(E3))

—Y—S—R^(E4),

—Z—CH₂—R^(E5), ora group shown below:

(wherein R^(E1) and R^(E2) are each independently, carbocyclic groupoptionally substituted by substituent group C, and heterocyclic groupoptionally substituted by substituent group C,R^(E3) is selected from a substituent group consisting of hydrogen,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C,R^(E4) is selected from a substituent group consisting of carbocyclelower alkyl optionally substituted by substituent group C, andheterocycle lower alkyl optionally substituted by substituent group C,R^(E5) is aromatic heterocyclic group optionally substituted bysubstituent group C,R^(E6) is selected from a substituent group C,m is an integer of 0 or more, provided thatm of R^(E6)s is same or different groups selected from a substituentgroup CY is straight or branched lower alkylene, andZ is a bond or straight or branched lower alkylene); andii) the other of R^(8a) or R^(10a) is,hydrogen, carboxy, cyano, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Y—S—R^(F1), —C(═O)—C(═O)—R^(F2), or

—C(═O)—N(RF^(F3))(R^(F4))(wherein R^(F1), R^(F2), R^(F3), and R^(F4) are each independently,hydrogen, lower alkyl optionally substituted by substituent group C,lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C, andY is straight or branched lower alkylene);Substituent group C: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocyclic group, heterocyclic group, carbocycle lower alkyloxy,heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocyclic group, heterocyclic group, carbocycle lower alkyloxy,heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxylower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC).

Item 14

The compound according to item 13, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A3))—SO₂—(R^(A4)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),—Z—N(R^(A20))—C(═O)—O—R^(A13), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(substituent group C, R^(A1), R^(A2), R^(A3), R^(A4), R^(A7), R^(A8),R^(A9), R^(A10), R^(A12), R^(A13), R^(A20), R^(A21), and Z are samemeaning as those of item 13).

Item 15

The compound according to item 13, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A7))—C(═O)—R^(A8), or—Z—N(R^(A12))—C(═O)—O—R^(A13)(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),and Z are same as those of item 13).

Item 16

The compound according to item 13, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, or—Z—N(R^(A1))(R^(A2))(substituent group C, R^(A1), R^(A2), and Z are same as those of item13).

Item 17

The compound according to item 13, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, or carboxy.

Item 18

The compound according to any one of items 13 to 17, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, or—Z—N(R^(B9))(R^(B10))(substituent group C, R^(B9), R^(B10), and Z are same as those of item13).

Item 19

The compound according to any one of items 13 to 17, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C(substituent group C is same as that of item 13).

Item 20

The compound according to any one of items 13 to 19, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(3a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,—Z—N(R^(C1))—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8)), or—Z—N(R^(C9))(R^(C10))(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), R^(C10), and Z are same as those of item 13).

Item 21

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a), andR^(5a), R^(6a) and R^(7a) are each independently hydrogen, carboxy,cyano, lower alkyl optionally substituted by substituent group C, loweralkenyl optionally substituted by substituent group C, lower alkynyloptionally substituted by substituent group C, lower alkyl carbonyloptionally substituted by substituent group C, lower alkyl oxycarbonyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1), —Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)), or—Z—C(R^(D7))(R^(D8))(R^(D9))(substituent group C, R^(D1), R^(D2), R^(D3), R^(D4), R^(D5), R^(D6),R^(D7), R^(D8), R^(D9), Y, and Z are same as those of item 13).

Item 22

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a),R^(6a) is hydrogen, andR^(5a) and R^(7a) are each independently hydrogen, lower alkyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C,

—Z—S—R^(D1), or

—Z—C(R^(D7))(R^(D8))(R^(D9))(substituent group C, R^(D1), R^(D7), R^(D8), R^(D9), and Z are same asitem 13).

Item 23

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a),R^(5a) is hydrogen, R^(6a) is hydrogen, andR^(7a) is lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C, or—Z—C(R^(D7))(R^(D8))(R^(D9))(substituent group C, R^(D7), R^(D8), R^(D9), and Z are same as item13).

Item 24

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a),R^(5a) is hydrogen, R^(6a) is hydrogen, andR^(7a) is a group shown below:

(wherein R^(E6) and m are same as those of item 13).

Item 25

The compound according to items 13 or 20, or the pharmaceuticallyacceptable salt thereof or the solvate thereof,

whereinB is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, and R^(11a) is hydrogen, andi) either R^(8a) or R^(10a) is—Z—C(R^(E1))(R^(E2))(R^(E3))

—Y—S—R^(E4)

—Z—CH₂—R^(E5),or a group shown below:

and,ii) the other of R^(8a) or R^(10a) ishydrogen, or lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,(Substituent group C is same as that of item 13).

—Z—S—R^(F1), —C(═O)—C(═O)—R^(F2), or

—C(═O)—N(R^(F3))(R^(F4))(substituent group C, R^(E1), R^(E2), R^(E3), R^(E4), R^(E5), R^(F1),R^(F2), R^(F3), R^(F4), R^(E6), m, Z, and Y are same as those of item13).

Item 26

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, R^(10a) is hydrogen, and R^(11a) is hydrogen,R^(8a) is —Z—CH(R^(E1))(R^(E2))(R^(E1), R^(E2) and Z are same as those of item 13).

Item 27

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(8a) is hydrogen, R^(9a) is hydrogen, and R^(11a) is hydrogen, andR^(10a) is —Z—CH(R^(E1))(R^(E2))(R^(E1), R^(E2), and Z are same as those of item 13).

Item 28

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, R^(10a) is hydrogen, and R^(11a) is hydrogen, andR^(8a) is a group shown below:

(wherein, R^(E6) and m are same as those of item 13).

Item 29

The compound according to any one of items 13 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, and R^(11a) is hydrogen,R^(8a) and R^(10a) may be taken together with an adjacent atom to formcarbocycle or heterocycle optionally substituted by substituent group D,(wherein substituent group D is same as that of item 13)

Item 30

The compound according to any one of items 13 to 19, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(5a)R^(6a), and B² is NR^(7a),R^(6a) is hydrogen,R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(5a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1), —C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(R^(D4))(wherein, R^(D1), R^(D2), R^(D3), and R^(D4) are each independentlyselected from a substituent group consisting of hydrogen, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,Y is straight or branched lower alkylene, and Substituent group C andsubstituent group D are same as those of item 13).

Item 31

The compound according to item 30, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein B¹ is CR^(5a)R^(6a), and B² is NR^(7a),R^(6a) is hydrogen,R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(5a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C (wherein substituent group C and substituentgroup D are same as those of item 13).

Item 32

The compound according to any one of items 13 to 19, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, and R^(10a) is hydrogen,R^(3a) and R^(11a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(8a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1), —C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(R^(D4))(wherein, R^(D1), R^(D2), R^(D3), and R^(D4) are each independentlyselected from a substituent group consisting of hydrogen, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,Y is straight or branched lower alkylene, and substituent group C andsubstituent group D are same as those of item 13).

Item 33

The compound according to item 32, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),R^(9a) is hydrogen, R^(10a) is hydrogen,R^(3a) and R^(11a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, andR^(8a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C) (wherein, substituent group C and substituentgroup D are same as those of item 13).

Item 34

The compound according to any one of items 29 to 33, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein substituent group D is carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C

Item 35

A pharmaceutical composition containing a compound according to any oneof items 13 to 34, or a pharmaceutically acceptable salt thereof or asolvate thereof.

Item 36

The pharmaceutical composition according to item 35 which exhibits CAPdependent endonuclease inhibitory activity.

Item 37

The pharmaceutical composition according to item 35 which exhibits antiinfluenza activity.

Item 38

A method for treating influenza infectious disease characterized inadministering the compound shown by formula (II) according to above item13, or the pharmaceutically acceptable salt thereof or the solvatethereof.

Item 39

Use of the compound shown by formula (II) according to above item 13, orthe pharmaceutically acceptable salt thereof or the solvate thereof, formanufacturing a therapeutic agent for influenza infectious disease.

Item 40

The compound shown by formula (II) according to above item 13, or thepharmaceutically acceptable salt thereof or the solvate thereof, fortreating influenza infectious disease.

Item 41

A method of producing a compound shown by formula (X4) or a saltthereof, comprising the steps of:

(Step B)

reacting a compound shown by formula (X2):

(wherein R^(1d) is hydrogen, halogen, lower alkyloxy optionallysubstituted by substituent E, carbocyclic group lower alkyloxyoptionally substituted by substituent E, heterocycle lower alkyloxyoptionally substituted by substituent E, or —OSi(R^(1e))₃,

R^(1e)s are each independently lower alkyl optionally substituted bysubstituent E, carbocyclic group optionally substituted by substituentE, heterocyclic group optionally substituted by substituent E,carbocycle lower alkyl optionally substituted by substituent E orheterocycle lower alkyl optionally substituted by substituent E,

R^(2d) is hydrogen, lower alkyl optionally substituted by substituent E,carbocycle lower alkyl optionally substituted by substituent E, orheterocycle lower alkyl optionally substituted by substituent E,

R^(3d) is hydrogen, lower alkyl optionally substituted by substituent E,—N(R^(3e))₂, or —OR^(3e),

R^(3e)s are each independently lower alkyl optionally substituted bysubstituent E,wavy line is E form and/or Z formSubstituent E: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo,nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclicgroup, heterocyclic group, carbocyclic group lower alkyloxy,heterocyclic group lower alkyloxy, halogeno lower alkyloxy, loweralkyloxy lower alkyl, lower alkyloxy lower alkyloxy, loweralkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylamino, lower alkylaminocarbonyl, loweralkylsulfonyl, and lower alkylsulfonylamino;with a compound shown by formula (V2):

(wherein R^(4d) is lower alkyl optionally substituted by substituent E,carbocycle lower alkyl optionally substituted by substituent E, orheterocycle lower alkyl optionally substituted by substituent E,R^(5d) is hydrogen, halogen, lower alkyloxy optionally substituted bysubstituent E, —O—SO₂—R^(5e), —O—SO₂—R^(5f), or —O—SO₂—R^(5g),R^(5e) is lower alkyl optionally substituted by substituent E,R^(5f) is carbocycle lower alkyl optionally substituted by substituentE, andR^(5g) is carbocycle lower alkyl optionally substituted by substituentE, andsubstituent E is defined above)to obtain a compound shown by formula (X3):

(wherein each symbol is defined above); and

(Step C)

reacting a compound shown by formula (X3) with a compound shown byformula (V3):

[Chemical formula 17]

H₂N—R^(6d)  (V3)

(wherein R^(6d) is lower alkyl optionally substituted by substituent E,or lower alkenyl optionally substituted by substituent E, andsubstituent E is defined above)to obtain a compound shown by formula (X4):

(wherein each symbol is defined above).

Item 42

A method according to item 41, wherein Step B and Step C arecontinuously performed.

Item 43

A method of producing a compound shown by formula (X3), or a saltthereof:

(wherein each symbol is defined in item 41)reacting a compound shown by formula (X2):

(wherein each symbol is defined in item 41)with a compound shown by formula (V2):

(wherein each symbol is defined in item 41).

Item 44

A method of producing a compound shown by formula (X4), or a saltthereof:

(wherein each symbol is defined in item 41)reacting a compound shown by formula (X3):

(wherein each symbol is defined in item 41); and with a compound shownby formula (V3):

[Chemical formula 23]

H₂N—R^(6d)  (V3)

(wherein symbol is defined in item 41).

Item 45

A method of producing a compound shown by formula (X4′), or a saltthereof:

(wherein each symbol is defined in item 41) comprising a step of:reacting a compound shown by formula (X2):

(wherein each symbol is defined in item 41)a compound shown by formula (V2):

(wherein each symbol is defined in item 41)and a compound shown by formula:

NH₄ ⁺X^(d−)  [Chemical formula 27]

(wherein X^(d) is halogen, CH₃COO, or HSO₄)

Item 46

A method of producing a compound shown by formula (X4), or a saltthereof:

(wherein each symbol is defined above) comprising the step of:reacting the compound shown by formula (X4′):

(wherein each symbol is defined above)obtained in the production method as defined in item 45, with a compoundshown by formula (V3′):

[Chemical formula 30]

R^(6d)-L^(d)  (V3′)

(wherein R^(6d) is defined above,L^(d) is halogen, —O—SO₂—CH₃, or —O—SO₂-Ph-CH₃, and Ph is a phenylgroup).

Item 47

A method according to any one of items 41, 43, and 45, wherein thecompound shown by formula (X2) is obtained by reacting a compound shownby formula (X1):

(wherein each symbol is defined above)with a compound shown by formula (V1):

(wherein P^(d) is lower alkyl optionally substituted by substituent E,and substituent E is defined in item 41).

Item 48

A compound shown by formula (X3):

(wherein each symbol is defined above),or a pharmaceutically acceptable salt thereof or solvate thereof.

Item 49

A compound shown by formula (X4):

(wherein each symbol is defined above),or a pharmaceutically acceptable salt thereof or solvate thereof.

Effect of the Invention

The compounds of this invention, having inhibitory activities tocap-dependent endonuclease, are effective as therapeutic agents and/orpreventive agents for influenza infectious disease.

BEST MODE FOR CARRYING OUT THE INVENTION

The meaning of each term used in the present description is explainedbelow. Each term is used in a unified sense, and is used in the samesense when used alone, or when used in combination of other term.

“Optionally substituted by substituent group A” means that an arbitraryposition may be substituted by one, two or more same or differentsubstituents selected from substituent group A.

“Optionally substituted by substituent group B”, “optionally substitutedby substituent group C”, “optionally substituted by substituent groupD”, and “optionally substituted by substituent group E” are also asdescribed above.

“Halogen” includes fluorine, chlorine, bromine and iodine. Preferable isfluorine, chlorine and bromine.

“Lower alkyl” includes straight or branched alkyl of a carbon number of1 to 15, preferably a carbon number of 1 to 10, more preferably a carbonnumber of 1 to 6, further preferably a carbon number of 1 to 4, andexamples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl,n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl etc.Examples of a preferable embodiment of “lower alkyl” include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,and n-pentyl. Examples of a further preferable embodiment includemethyl, ethyl, n-propyl, isopropyl, and tert-butyl.

“Lower alkenyl” includes straight or branched alkenyl of a carbon numberof 2 to 15, preferably a carbon number of 2 to 10, more preferably acarbon number of 2 to 6, further preferably a carbon number of 2 to 4,having one or more double bonds at an arbitrary position. Specifically,lower alkenyl includes vinyl, allyl, propenyl, isopropenyl, butenyl,isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl,hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc.Examples of a preferable embodiment of “lower alkenyl” include vinyl,allyl, propenyl, isopropenyl, and butenyl.

“Lower alkynyl” includes straight or branched alkynyl of a carbon numberof 2 to 10, preferably a carbon number of 2 to 8, further preferably acarbon number of 3 to 6, having one or more triple bonds at an arbitraryposition. Specifically, lower alkynyl includes ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc.These may further have a double bond at an arbitrary position. Examplesof a preferable embodiment of “lower alkynyl” include ethynyl, propynyl,butynyl, and pentynyl.

A lower alkyl part of “lower alkyloxy”, “lower alkylcarbonyl”, “loweralkyloxycarbonyl”, “carbocycle lower alkyl”, “heterocycle lower alkyl”,“carbocycleoxy lower alkyl”, “heterocycleoxy lower alkyl”, “halogenolower alkyl”, “carbocycle lower alkyloxy”, “heterocycle lower alkyloxy”,“halogeno lower alkyloxy”, “lower alkyloxy lower alkyl”, “lower alkyloxylower alkyloxy”, “lower alkylcarbonyl”, “lower alkyloxycarbonyl”, “loweralkylamino”, “lower alkylcarbonylamino”, “lower alkylaminocarbonyl”,“lower alkylsulfonyl”, “lower alkylsulfonylamino”, “lower alkylthio”,“hydroxy lower alkyl”, “carbocycle lower alkyloxy lower alkyl”,“heterocycle lower alkyloxy lower alkyl”, “lower alkylcarbonyloxy”,“halogeno lower alkylcarbonylamino”, and “lower alkylsulfinyl” is thesame as the “lower alkyl” as described above.

A lower alkenyl part of “lower alkenyloxy” is the same as the “loweralkenyl” as described above.

A halogen part of “halogeno lower alkyl”, “halogeno lower alkyloxy”, and“halogeno lower alkylcarbonylamino” is the same as the “halogen”.Herein, an arbitrary position on an alkyl group of “lower alkyl”, “loweralkyloxy”, and “lower alkylcarbonylamino” may be substituted by same ordifferent one or plural halogen atoms, respectively.

“Carbocyclic group” or “carbocycle” means carbocyclic group of a carbonnumber of 3 to 20, preferably a carbon number of 3 to 16, morepreferably a carbon number of 4 to 12, and includes cycloalkyl,cycloalkenyl, aryl and a non-aromatic condensed carbocyclic group, etc.

Specifically, “cycloalkyl” is carbocyclic group of a carbon number of 3to 16, preferably a carbon number of 3 to 12, more preferably a carbonnumber of 4 to 8, and examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl andcyclodecyl, etc.

Specifically, “cycloalkenyl” includes cycloalkenyl having one or moredouble bonds at an arbitrary position in the cycloalkyl ring, andexamples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptynyl, cyclooctynyl and cyclohexadienyl, etc.

Specifically, “aryl” includes phenyl, naphthyl, anthryl and phenanthryl,etc. and, particularly, phenyl is preferable.

Specifically, “non-aromatic condensed carbocyclic group” includes agroup in which two or more cyclic groups selected from the “cycloalkyl”,the “cycloalkenyl” and the “aryl” are condensed, and examples includeindanyl, indenyl, tetrahydronaphthyl, fluorenyl, adamantyl, and a groupshown below:

etc.

Examples of a preferable embodiment of “carbocyclic group” or“carbocycle” include cycloalkyl, aryl and a non-aromatic condensedcarbocyclic group, specifically examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, anda group shown below:

etc.

A carbocyclic part of “carbocycle lower alkyl”, “carbocycle loweralkyloxy”, “carbocycleoxy lower alkyl”, “carbocyclecarbonyl”,“carbocycleoxy”, “carbocycleoxycarbonyl” and “carbocycle lower alkyloxylower alkyl” is the same as the “carbocyclic group” or the “carbocycle”as described above.

“Heterocyclic group” or “heterocycle” includes heterocyclic group suchas heteroaryl, a non-aromatic heterocyclic group, a bicyclic condensedheterocyclic group, a tricyclic condensed heterocyclic group, etc.,having one or more same or different hetero atoms arbitrarily selectedfrom O, S and N in a ring.

Specifically, “heteroaryl” includes a 5- to 6-membered aromatic cyclicgroup such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isooxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,thiadiazolyl, etc.

Specifically, “non-aromatic heterocyclic group” includes a 4- to8-membered non-aromatic heterocyclic group such as dioxanyl, thiiranyl,oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl,tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl,hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl,hexahydropyrimidinyl, dioxolanyl, etc.

Specifically, “bicyclic condensed heterocyclic group” includes a cyclicgroup including at least one 4- to 8-membered aromatic or non-aromaticheterocyclic group such as indolyl, isoindolyl, indazolyl, indolizinyl,indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl,pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisooxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl,imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotrianizyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl,naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxynyl, dihydrobenzooxezinyl, dihydrobenzodioxepinyl,dihydrothienodioxynyl, etc.

Specifically, “tricyclic condensed heterocyclic group” includes a cyclicgroup including at least one 4- to 8-membered aromatic or non-aromaticheterocyclic group such as carbazolyl, acridinyl, xanthenyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl,imidazoquinolyl, tetrahydrocarbazolyl, and a group shown below:

etc.

Examples of a preferable embodiment of “heterocyclic group” include 5-to 6-membered heteroaryl, a non-aromatic heterocyclic group and atricyclic condensed heterocyclic group.

A heterocyclic part of “heterocycle lower alkyl”, “heterocycle loweralkyloxy”, “carbocycleoxy lower alkyl”, “heterocyclecarbonyl”,“heterocycleoxy”, “heterocycleoxycarbonyl”, and “heterocycle loweralkyloxy lower alkyl” is the same as the “heterocyclic group” or the“heterocycle” as described above.

“Heterocyclic group substituted by oxo” means the “heterocyclic group”as described above, substituted by oxo as shown below. A group shownbelow:

is exemplified.

“Straight or branched lower alkylene” is divalent “lower alkyl” asdescribed above, and includes, for example, methylene, ethylene,propylene, butylene, isobutylene, pentylene, heptylene,dimethylmethylene, ethylmethylmethylene, 1,2-dimethylethylene, etc.

Examples of “lower alkyloxy” include methoxy, ethoxy, propyloxy,isopropyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, etc. Examples of a preferable embodiment includemethoxy, ethoxy, propyloxy, isopropyloxy, and tert-butyloxy.

Examples of “lower alkylcarbonyl” include methylcarbonyl, ethylcarbonyl,propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl,sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl,etc. Examples of a preferable embodiment include methylcarbonyl,ethylcarbonyl, and propylcarbonyl.

Examples of “lower alkyloxycarbonyl” include methyloxycarbonyl,ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. Examplesof a preferable embodiment include methyloxycarbonyl, ethyloxycarbonyl,and propyloxycarbonyl.

“Carbocycle lower alkyl” represents lower alkyl substituted by one, twoor more carbocyclic groups, and examples of “carbocycle lower alkyl”include benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, naphthylmethyl, a group shown below:

etc. Examples of a preferable embodiment include benzyl, phenethyl, andbenzhydryl.

“Heterocycle lower alkyl” represents lower alkyl substituted by one, twoor more heterocyclic groups, and also includes heterocycle lower alkylin which an alkyl part is substituted by carbocyclic group. Examples of“heterocycle lower alkyl” include pyridylmethyl,tetrahydropyranylmethyl, furanylmethyl, morpholinylethyl,imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl,isooxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl,isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl,piperidinylmethyl, piperazinylmethyl, a group shown below:

etc. Examples of a preferable embodiment include pyridylmethyl,tetrahydropyranylmethyl, furanylmethyl, and morpholinylethyl.

Examples of “carbocycleoxy lower alkyl” include phenyloxymethyl,phenyloxyethyl, cyclopropyloxymethyl, cyclopropyloxyethyl,cyclobutyloxymethyl, cyclobutyloxyethyl, cyclohexyloxymethyl,cyclohexyloxyethyl, etc. Examples of a preferable embodiment includephenyloxymethyl, and phenyloxyethyl.

Examples of “heterocycleoxy lower alkyl” include pyridyloxymethyl,pyridyloxyethyl, morpholinyloxymethyl, morpholinyloxyethyl,benzoxazolyloxymethyl, etc. Examples of a preferable embodiment includepyridyloxymethyl, morpholinyloxymethyl, etc.

“Carbocycle lower alkyloxy” represents lower alkyloxy in which an alkylpart is substituted by one, two or more carbocyclic groups, and examplesof “carbocycle lower alkyloxy” include phenylmethyloxy, phenylethyloxy,cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy, etc. Examples of a preferable embodiment includephenylmethyloxy, cyclopropylmethyloxy, etc.

“Heterocycle lower alkyloxy” represents lower alkyloxy in which an alkylpart is substituted by one, two or more heterocyclic groups, and alsoincludes heterocycle lower alkyloxy in which an alkyl part issubstituted by carbocyclic group. Examples of “heterocycle loweralkyloxy” include pyridylmethyloxy, pyridylethyloxy,imidazolylmethyloxy, imidazolylethyloxy, benzoxazolylmethyloxy,benzoxazolylethyloxy, etc.

Examples of “lower alkyloxy lower alkyl” include methoxymethyl,methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl,ethoxypropyl, ethoxybutyl, isopropyloxymethyl, tert-butyloxymethyl, etc.Examples of a preferable embodiment include methoxymethyl, methoxyethyl,ethoxymethyl, and ethoxyethyl.

Examples of “lower alkyloxy lower alkyloxy” include methoxymethoxy,methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxypropyloxy,methoxybutyloxy, ethoxypropyloxy, ethoxybutyloxy, isopropyloxymethyloxy,tert-butyloxymethyloxy, etc. Examples of a preferable embodiment includemethoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.

Examples of “lower alkylamino” include methylamino, dimethylamino,ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino,N-methyl-N-ethylamino, N-isopropyl-N-ethylamino, etc. Examples of apreferable embodiment include methylamino, dimethylamino, ethylamino,and diethylamino.

Examples of “lower alkylcarbonylamino” include methylcarbonylamino,ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino,tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino,etc. Examples of a preferable embodiment include methylcarbonylamino,and ethylcarbonylamino.

Examples of “lower alkylaminocarbonyl” include methylaminocarbonyl,dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl,isopropylaminocarbonyl, N,N-diisopropylaminocarbonyl,N-methyl-N-ethylaminocarbonyl, N-isopropyl-N-ethylaminocarbonyl, etc.Examples of a preferable embodiment include methylaminocarbonyl,dimethylaminocarbonyl, ethylaminocarbonyl, and diethylaminocarbonyl.

Examples of “lower alkylsulfonyl” include methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl, etc. Examples of a preferable embodiment includemethylsulfonyl, and ethylsulfonyl.

Examples of “lower alkylsulfonylamino” include methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino,etc. Examples of a preferable embodiment include methylsulfonylamino,and ethylsulfonylamino.

Examples of “lower alkenyloxy” include ethylenyloxy, 1-propylenyloxy,2-propylenyloxy, 1-butylenyloxy, 2-butylenyloxy, 3-butylenyloxy, etc.

Examples of “halogeno lower alkyl” include monofluoromethyl,monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl,monochloromethyl, trifluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl,1,1,1-trifluoropropan-2-yl, etc. Examples of a preferable embodimentinclude trifluoromethyl, trichloromethyl, 1,1,1-trifluoropropan-2-yl.

Examples of “halogeno lower alkyloxy” include monofluoromethoxy,monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy,trichloroethoxy, etc. Examples of a preferable embodiment includetrifluoromethoxy, and trichloromethoxy.

Examples of “lower alkylthio” include methylthio, ethylthio, propylthio,etc.

Examples of “hydroxy lower alkyl” include hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.

Examples of “carbocycle lower alkyloxy lower alkyl” includebenzyloxymethyl, benzyloxyethyl, benzhydryloxymethyl, etc.

Examples of “heterocycle lower alkyloxy lower alkyl” includepyridylmethyloxymethyl, pyridylmethyloxyethyl, etc.

Examples of “lower alkylcarbonyloxy” include methylcarbonyloxy,ethylcarbonyloxy, etc.

Examples of “halogeno lower alkylcarbonylamino” includetrifluoromethylcarbonylamino, 2,2,3,3,3-pentafluoropropylcarbonylamino,etc.

Examples of “lower alkylsulfinyl” include methylsulfinyl, ethylsulfinyl,etc.

Examples of “carbocyclecarbonyl” include phenylcarbonyl,naphthylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

Examples of “carbocycleoxy” include phenyloxy, naphthyloxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

Examples of “carbocycleoxycarbonyl” include phenyloxycarbonyl,naphthyloxycarbonyl, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.

Examples of “heterocyclecarbonyl” include pyridylcarbonyl,benzoxazolylcarbonyl, morpholinylcarbonyl, tetrahydropyranylcarbonyl,etc.

Examples of “heterocycleoxy” include pyridyloxy, benzoxazolyloxy,morpholinyloxy, tetrahydropyranyloxy, etc.

Examples of “heterocycleoxycarbonyl” include pyridyloxycarbonyl,benzoxazolyloxycarbonyl, morpholinyloxycarbonyl,tetrahydropyranyloxycarbonyl, etc.

“R^(X1) and R^(X2), R^(X9) and R^(X10), R^(X17) and R^(X18) as well asR^(X20) and R^(X21), each may be taken together with an adjacent atom toform a heterocycle”,“R^(Y7) and R^(Y8), as well as R^(Y9) and R^(Y10), each may be takentogether with an adjacent atom to form a heterocycle”,“R^(Z7) and R^(Z8), as well as R^(Z9) and R^(Z10), each may be takentogether with an adjacent atom to form a heterocycle”, and“R^(V5) and R^(V6) may be taken together with an adjacent atom to form aheterocycle” in item 1′ and item 1; and“R^(A1) and R^(A2), R^(A15) and R^(A16), as well as R^(A19) and R^(A20),each may be taken together with an adjacent atom to form a heterocycle”,“R^(B7) and R^(B8), as well as R^(B9) and R^(B10), each may be takentogether with an adjacent atom to form a heterocycle”,“R^(C7) and R^(C8), as well as R^(C9) and R^(C10), each may be takentogether with an adjacent atom to form a heterocycle”, and“R^(D5) and R^(D6) may be taken together with an adjacent atom to form aheterocycle” in item 13′ and item 13 mean a heterocycle having N atom,and include, for example, a group shown below:

etc.

In the present description, (R^(E6))m in the formula shown below:

means that an arbitrary carbon atom or nitrogen atom which canchemically have a substituent on a ring is substituted by m of R^(E6)swhich are same or different.

For example, in the formula below:

as shown by a substituent below:

(wherein ma+mb+mc=m, and R^(E6) is as defined above), it is meant thatany hydrogen atom on two benzene rings and a 7-membered ring containinga sulfur atom may be substituted by R^(E6), and respective R^(E6)s maybe the same or different.

And, ma is preferably an integer of 0 to 3, mb is preferably an integerof 0 to 3, and mc is preferably an integer of 0 or 1. And, ma is morepreferably an integer of 0 or 1, mb is more preferably an integer of 0or 1, and mc is more preferably 0.

For example, in the formula below:

substituents shown below:

(wherein R^(E6), and m are as defined in item 13′)etc. are included.

“When A¹ is CR⁵R⁶, and A² is NR⁷, R³ and R⁷ may be taken together withan adjacent atom to form a heterocycle optionally substituted bysubstituent group B” in the formula (I) in item 1′ and item 1 representsthe formula (I′) shown below:

(wherein R¹, R², R⁵ and R⁶ are as defined in item 1′ and item 1), andindicates that the “ring” may be substituted by one, two or more same ordifferent substituents selected from substituent group B at an arbitraryposition. The heterocycle is preferably a 5- to 7-membered ring. Inaddition, “the heterocycle may form a condensed ring” indicates that thering in the formula (I′) may be further condensed with a ring, andindicates that substituent group B may be bound to any of the ring inthe formula (I′) or the ring which is condensed with a ring. Examples ofthe formula (I′) include compounds shown by the following formulae:

(wherein R^(x), and R^(y) are a substituent selected from substituentgroup B, and R¹, R², R⁵, and R⁶ are as defined in item 1′ and item 1)etc.

“When form a heterocycle” in “when A¹ is NR⁷, and A² is CR⁵R⁶, R³ and R⁶may be taken together with an adjacent atom to form a heterocycleoptionally substituted by substituent group B” in the formula (I) initem 1′ and item 1 represents the formula (I″) shown below:

(wherein R¹, R², R⁵, and R⁶ are as defined in item 1′ and item 1), andindicates that a part of a ring may be substituted by one, two or moresame or different substituents selected from substituent group B at anarbitrary position. The heterocycle is preferably a 5- to 7-memberedring. In addition, “the heterocycle may form a condensed ring” indicatesthat the ring in the formula (I″) may be further condensed with a ring,and indicates that one, two or more of substituent group B may be boundto any of the ring in the formula (I″) or the ring which is condensedwith a ring. Examples of the formula (I″) include compounds shown in thefollowing formula:

(wherein R^(x) an R^(y) are a substituent selected from substituentgroup B, and R¹, R², R⁵ and R⁷ are as defined in item 1′ and item 1)etc.

“When form a bond” in “when A¹ is CR⁸R⁹, and A² is CR¹⁰R¹¹, R⁸ and R¹⁰may be taken together with an adjacent atom to form a bond” in theformula (I) of item 1′ and item 1 represents the formula (I′″) shownbelow:

(wherein R¹, R², R³, R⁹ and R¹¹ are as defined in item 1′ and item 1).

In addition, “when form a bond” in “R⁸ and R¹⁰ may be taken togetherwith an adjacent atom to form a carbocycle or a heterocycle optionallysubstituted by substituent group B″ represents the formula (I″″) shownbelow:

(wherein R¹, R², R³, R⁹ and R¹¹ are as defined in item 1′ and item 1),and indicates that a part of a ring may be substituted by one, two ormore same or different substituents selected from substituent group B atan arbitrary position. The carbocycle or the heterocycle is preferably a5- to 7-membered ring. Examples of the formula (I″″) include a compoundshown in the following formula:

(wherein R^(x) and R^(y) are a substituent selected from substituentgroup B, and R¹, R², R³, R⁹ and R¹¹ are as defined in item 1′ anditem 1) etc.

Further, “R³ and R¹¹ may be taken together with an adjacent atom to forma heterocyle optionally substituted by substituent group B, and theheterocycle may form a condensed ring” represents the formula (I′″″)shown below:

(wherein R¹, R², R⁸, R⁹ and R¹⁰ are as defined in item 1′ and item 1),and indicates that a part of a ring may further form a condensed ring,and the same or different substituents selected from substituent group Bmay be bound to any of the ring in the formula (I′″″) or the ring whichis condensed with a ring at an arbitrary position. The heterocycle ispreferably a 5- to 7-membered ring. Examples of the formula (I′″″)include compounds shown by the following formula:

(wherein R^(x) and R^(y) are a substituent selected from substituentgroup B, and R¹, R², R⁸, R⁹ and R¹⁰ are as defined in item 1′ anditem 1) etc.

“When form a heterocyle” in “when B¹ is CR^(5a)R^(6a), and B² isNR^(7a), R^(3a) and R^(7a) may be taken together with an adjacent atomto form a heterocycle optionally substituted by substituent group D” inthe formula (II) in item 13 represents the formula (II′) shown below:

(wherein R^(1a), R^(2a), R^(5a) and R^(6a) are as defined in item 13′and item 13).

“When form a heterocycle” in “when B¹ is NR^(7a), and B² isCR^(5a)R^(6a), R^(3a) and R^(6a) may be taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupD” represents the formula (II″) shown below:

(wherein R^(1a), R^(2a), R^(5a) and R^(7a) are as defined in item 13′and item 13). The heterocycle is preferably a 5- to 7-membered ring.

“When form a heterocycle” in “when B¹ is CR^(8a)R^(9a), and B² isCR^(10a)R^(11a), R^(8a) and R^(10a) may be taken together with anadjacent atom to form a carbocycle or a heterocycle optionallysubstituted by substituent group D” represents the formula (II′″) shownbelow:

(wherein R^(1a), R^(2a), R^(3a), R^(9a) and R^(11a) are as defined initem 13′ and item 13). The carbocycle or the heterocycle is preferably a5- to 7-membered ring.

“When form a heterocycle” in “when B¹ is CR^(8a)R^(9a), and B² isCR^(10a)R^(11a), R^(3a) and R^(11a) may be taken together with anadjacent atom to form a heterocycle optionally substituted bysubstituent group D” represents the formula (II″″) shown below:

(wherein R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) are as defined initem 13′ and an item 13). The heterocycle is preferably a 5- to7-membered ring.

“Solvate” includes, for example, a solvate with an organic solvent, ahydrate, etc. When a hydrate is formed, the compound may be coordinatedwith an arbitrary number of water molecules.

The compound of the present invention includes a pharmaceuticallyacceptable salt. Examples include salts with an alkali metal (lithium,sodium or potassium, etc.), an alkaline earth metal (magnesium orcalcium, etc.), ammonium, an organic base and an amino acid, or saltswith an inorganic acid (hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid or hydroiodic acid, etc.), and anorganic acid (acetic acid, trifluoroacetic acid, citric acid, lacticacid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelicacid, glutaric acid, malic acid, benzoic acid, phthalic acid,benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid orethanesulfonic acid, etc.). These salts can be formed by the methodwhich is usually performed.

In addition, the compound of the present invention is not limited to aparticular isomer, but includes all possible isomers (keto-enol isomer,imine-enamine isomer, diastereoisomer, optical isomer and rotationisomer, etc.) and racemic bodies.

The formula (I) and the formula (II) in the present invention are notlimited to a particular isomer, but include all possible isomers andracemic bodies. For example, they contain a tautomer and a steric isomeras follows.

Further in the formula (I) and the formula (II) of the presentinvention, one or more hydrogen atoms, carbon atoms or other atoms canbe substituted by an isotope of a hydrogen atom, a carbon atom or otheratoms, respectively.

In addition, the compounds of the formulae (I) and (II) include allradioactive labeled bodies thereof. Such the “radioactive labeling” and“radioactive labeled form” of the compounds of the formulae (I) and (II)are included in the present invention, respectively, and are useful as astudy and/or diagnostic tool in metabolized drug dynamic state study andbinding assay.

Examples of an isotope which can be incorporated into the compounds ofthe formulae (I) and (II) of the present invention include a hydrogenatom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom,a sulfur atom, a fluorine atom and a chlorine atom, such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

A particularly preferable example of an isotope which can beincorporated into the compounds of the formulae (I) and (II) of thepresent invention is ²H (i.e. heavy hydrogen atom), and can be preparedby the method shown in Examples of the present description, or themethod well-known in the art. In addition, a heavy hydrogen atom isexpressed as “D” in Examples of the present description. Compounds ofthe formulae (I) and (II) of the present invention in which a hydrogenatom has been converted into a heavy hydrogen atom are excellent inrespect of bioavailability, metabolism safety, drug efficacy, andtoxicity as compared with unconverted forms, in some cases, and can beuseful as medicaments.

“step B and step C are continuously performed” refers to execution ofstep C after reaction of step B without isolation operation and columnchromatography purification of product generated in step B. A reactioncontainer for step B and a reaction container for step C may be the sameor different.

Examples of “lower alkyl optionally substituted by substituent group A”and “lower alkyl optionally substituted by substituent group C” includemethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,pentan-2-yl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl,carboxypropyl, ethoxycarbonylpropyl, cyanomethyl, cyanoethyl,fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,ethyloxycarbonylethyl, methoxymethyl, dimethoxymethyl, methoxyethyl,methoxypropyl, ethoxyethyl, 1-methyl-1-methoxymethyl, propyloxymethyl,aminopropyl, dimethylaminomethyl, aminomethyl, aminoethyl,dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl,dimethylaminopropyl, cyclopropylmethyloxymethyl,methylsulfonylaminomethyl, methylaminocarbonylethyl,1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl,1,1,1-trifluoropropyl, trifluoromethyloxyethyl,trifluoromethylcarbonylaminomethyl, methylsulfonylethyl,methylcarbonyloxyethyl, and groups shown below:

Chemical Formula 63

etc.

Examples of “lower alkenyl optionally substituted by substituent groupA” and “lower alkenyl optionally substituted by substituent group C”include ethylenyl, 3-methylbuten-2-yl, carboxyethylenyl,hydroxyethylenyl, difluoroethylenyl, 1-propen-2-yl, etc.

Examples of “lower alkynyl optionally substituted by substituent groupA” and “lower alkynyl optionally substituted by substituent group C”include 1-propynyl, 1-butynyl, 3,3,3-trifluoromethylpropynyl,3-hydroxy-propynyl, etc.

Examples of “lower alkyloxy optionally substituted by substituent groupA” and “lower alkyloxy optionally substituted by substituent group C”include methyloxy, ethyloxy, trifluoromethyloxy, trichloromethyloxy,hydroxymethyloxy, hydroxyethyloxy, carboxymethyloxy, carboxyethyloxy,etc.

Examples of “lower alkenyloxy optionally substituted by substituentgroup A” and “lower alkenyloxy optionally substituted by substituentgroup C” include 3-fluoro-1-propenyloxy, ethylenyl, carboxyethylenyl,hydroxyethylenyloxy, difluoroethylenyloxy, etc.

Examples of “lower alkylcarbonyl optionally substituted by substituentgroup A” and “lower alkylcarbonyl optionally substituted by substituentgroup C” include methylcarbonyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl,trifluoromethylcarbonyl, 2,2,2-trifluoromethylcarbonyl,carboxymethylcarbonyl, etc.

Examples of “lower alkyloxycarbonyl optionally substituted bysubstituent group A” and “lower alkyloxycarbonyl optionally substitutedby substituent group C” include methyloxycarbonyl, ethyloxycarbonyl,trifluoromethyl oxycarbonyl, trichloromethyloxycarbonyl,hydroxymethyloxycarbonyl, hydroxyethyloxycarbonyl,carboxymethyloxycarbonyl, etc.

Examples of “carbocyclic group optionally substituted by substituentgroup A” and “carbocyclic group optionally substituted by substituentgroup C” include phenyl, naphthyl, anthracenyl, phenanthracenyl,adamantyl, 1-hydroxyadamantyl, 2-hydroxyadamantyl, 3-methylphenyl,4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, fluorocyclopropyl, difluorocyclobutanyl,difluorocyclohexyl, and groups shown below:

(wherein R^(E6) represents a group selected from substituent group A orsubstituent group C, and m of R^(E6)s may be the same or different) etc.

Examples of “carbocycle lower alkyl optionally substituted bysubstituent group A” and “carbocycle lower alkyl optionally substitutedby substituent group C” include cyclopropylmethyl, 4-hydroxybenzyl,cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl, 2-fluorobenzyl,4-fluorobenzyl, 2-trifluoromethylbenzyl, 1,3,5-trifluorobenzyl,3,4,5-trifluorobenzyl, 4-methoxybenzyl, 2,4-difluorobenzyl,2-fluoro-3-chlorobenzyl, benzhydryl, 4-phenylbenzyl, phenethyl,phenylpropyl, 4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl,4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, and groups shown below:

etc.

Examples of “carbocycric oxy lower alkyl optionally substituted bysubstituent group A” and “carbocycleoxy lower alkyl optionallysubstituted by substituent group C” include 4-hydroxyphenyloxymethyl,4-hydroxyphenyloxyethyl, cyclopropyloxymethyl, cyclopentyloxymethyl,4-fluorophenyloxymethyl, 4-fluorophenyloxyethyl,4-trifluoromethylphenyloxymethyl, 4-trifluoromethylphenyloxyethyl,4-methoxyphenyloxymethyl, 4-methoxyphenyloxyethyl, etc.

Examples of “carbocyclecarbonyl optionally substituted by substituentgroup A” and “carbocyclecarbonyl optionally substituted by substituentgroup C” include phenylcarbonyl, 4-fluorophenylcarbonyl,4-trifluoromethylphenylcarbonyl, 4-methoxyphenylcarbonyl,cyclopropylcarbonyl, etc.

Examples of “carbocycleoxy optionally substituted by substituent groupA” and “carbocycleoxy optionally substituted by substituent group C”include phenyloxy, cyclopropyloxy, cyclopentyloxy, 4-fluorophenyloxy,4-trifluoromethylphenyloxy, 4-methoxyphenyloxy, etc.

Examples of “carbocycleoxycarbonyl optionally substituted by substituentgroup A” and “carbocycleoxycarbonyl optionally substituted bysubstituent group C” include phenyloxycarbonyl, cyclopropyloxycarbonyl,cyclopentyloxycarbonyl, 4-fluorophenyloxycarbonyl,4-trifluoromethylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl, etc.

Examples of “heterocyclic group optionally substituted by substituentgroup A” and “heterocyclic group optionally substituted by substituentgroup C” include pyrimidinyl, pyridyl, benzoxazolyl, morpholinyl,tetrahydropyranyl, furyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl,methylpyrrolidinyl, isopropylpyrrolidinyl, methylsulfonylpyrrolidinyl,hydroxyethylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl,tetrahydrofuryl, and groups shown below:

(wherein R^(E6) represents a group selected from substituent group A orsubstituent group C, and m of R^(E6)s may be the same or different) etc.

Examples of “heterocycle lower alkyl optionally substituted bysubstituent group A” and “heterocycle lower alkyl optionally substitutedby substituent group C” include tetrahydropyranylmethyl, pyridylmethyl,isoxazolylmethyl, 5-methyl-isoxazolylmethyl, 3-methyl-oxadiazolylmethyl,indolylmethyl, benzothiophenylmethyl, 5-chlorobenzothiophenylmethyl,thiazolylmethyl, 2-methylthiazolylmethyl, pyrazolylmethyl,2-methylpyrazolylmethyl, dithiophenylmethyl, tetrazolylmethyl,quinazolylmethyl, and groups shown below:

etc.

Examples of “heterocycleoxy lower alkyl optionally substituted bysubstituent group A” and “heterocycleoxy lower alkyl optionallysubstituted by a substutuent group C” includetetrahydropyranyloxymethyl, pyridyloxymethyl, isoxazolyloxymethyl,5-methyl-isoxazolyloxymethyl, indolyloxymethyl,benzothiophenyloxymethyl, 5-chlorobenzothiophenyloxymethyl,thiazolyloxymethyl, 2-methylthiazolyloxymethyl, pyrazolyloxymethyl,2-methylpyrazolyloxymethyl, etc.

Examples of “heterocyclecarbonyl optionally substituted by substituentgroup A” and “heterocyclecarbonyl optionally substituted by substituentgroup C” include tetrahydropyranylcarbonyl, pyridylcarbonyl,isoxazolylcarbonyl, 5-methyl-isoxazolylcarbonyl, indolylcarbonyl,benzothiophenylcarbonyl, 5-chlorobenzothiophenylcarbonyl,thiazolylcarbonyl, 2-methylthiazolylcarbonyl, pyrazolylcarbonyl,2-methylpyrazolylcarbonyl, etc.

Examples of “heterocycleoxy optionally substituted by substituent groupA”, and “heterocycleoxy optionally substituted by substituent C” includetetrahydropyranyloxy, pyridyloxy, isoxazolyloxy, 5-methyl-isoxazolyloxy,indolyloxy, benzothiophenyloxy, 5-chlorobenzothiophenyloxy,thiazolyloxy, 2-methylthiazolyloxy, pyrazolyloxy, 2-methylpyrazolyloxy,etc.

Examples of “heterocycleoxycarbonyl optionally substituted bysubstituent group A”, and “heterocycleoxycarbonyl optionally substitutedby substituent group C” include tetrahydropyranyloxycarbonyl,pyridyloxycarbonyl, isoxazolyloxycarbonyl,5-methyl-isoxazolyloxycarbonyl, indolyloxycarbonyl,benzothiophenyloxycarbonyl, 5-chlorobenzothiophenyloxycarbonyl,thiazolyloxycarbonyl, 2-methylthiazolyloxycarbonyl,pyrazolyloxycarbonyl, 2-methylpyrazolyloxycarbonyl, etc.

Examples of a preferable substituent in R¹ and R^(1a) include hydrogen,halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(A1))(R^(A2))—Z—N(R^(A3))—SO₂—(R^(A4))—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R^(A11),

—Z—N(R^(A12))—C(═O)—O—R^(A13),—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or—Z—N(R^(A2))—C(═O)—C(═O)—R^(A21),(substituent group C, R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8),R^(A9), R^(A10), R^(A11), R^(A12), R^(A13), R^(A14), R^(A15), R^(A16),R^(A17), R^(A18), R^(A19), R^(A20), R^(A21), and Z are as defined initem 13′ or item 13).

Examples of a more preferable substituent in R¹ and R^(1a) includehydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substitutedby substituent group C, lower alkenyl optionally substituted bysubstituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C,

—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A7))—C(═O)—R^(A8), or—Z—N(R^(A12))—C(═O)—O—R^(A13)(Substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13)and Z are as defined in item 13′ or item 13)

Examples of a further preferable substituent in R¹ and R^(1a) includehydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substitutedby substituent group C, lower alkenyl optionally substituted bysubstituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, or

—Z—N(R^(A1))(R^(A2))(substituent group C, R^(A1), R^(A2), and Z are as defined in item 13′or item 13)

Examples of another embodiment of a preferable substituent in R¹ andR^(1a) include hydrogen, carboxy, hydroxymethyl, methoxy, chlorine atom,bromine atom, ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)₂-Me,amino, methylamino, methylaminomethyl, —NH—C(═O)—CF₃, pyrazolyl,—NH—C(═O)-Me, —C(═O)N-Me₂, tetrazolyl, —NH—C(═O)-Ph, —C(═O)NH-Me,—C(═O)NH-Et, —C(═O)NH-cyclopropyl, methoxycarbonyl, methyl, propenyl,propyl, isopropyl, fluoromethyl

(Me represents a methyl group, Ph represents a phenyl group, and Etrepresents an ethyl group) etc.

Examples of another embodiment of a more preferable substituent in R¹and R^(1a) include hydrogen, carboxy, hydroxymethyl, methoxy, bromineatom, ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)₂-Me, amino,methylamino, methyl, propenyl

(Me represents a methyl group) etc.

Examples of another embodiment of a further preferable substituent in R¹and R^(1a) include hydrogen, and carboxy.

Examples of a preferable substituent in R² and R^(2a) include hydrogen,halogen, carboxy, cyano, formyl, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkyloxy optionally substituted by substituent group C, loweralkenyloxy optionally substituted by substituent group C, loweralkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxy optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(B1))—SO₂—R^(B2),—Z—N(R^(B3))—C(═O)—R^(B4),—Z—N(R^(B5))—C(═O)—O—R^(B6),—Z—C(═O)—N(R^(B7))(R^(B8)),—Z—N(R^(B9))(R^(B10)), or—Z—SO₂—R^(B11)(substituent group C, R^(B1), R^(B2), R^(B3), R^(B4), R^(B5), R^(B6),R^(B7), R^(B8), R^(B9), R^(B10), R^(B11) and Z are as defined in item13′ or item 13).

Examples of a more preferable substituent in R² and R^(2a) includehydrogen, lower alkyl optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or

—Z—N(R^(B9))(R^(B10))(a substituent group C, R^(B9), R^(B10), and Z are as defined in item13′ or item 13).

Examples of a further preferable substituent in R² and R^(2a) includehydrogen, or lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C(substituent group C is as defined in item 13′ or item 13).

Examples of another embodiment of a preferable substituent in R² andR^(2a) include hydrogen, hydroxymethyl, amino, methoxymethyl,methoxymethylcyclopropylmethyloxymethyl, cyanomethyl, aminomethyl,propyloxymethyl, —CH₂—NH—C(═O)-Me, methylaminomethyl, imidazolyl,dimethylaminomethyl, pyrrolidinyl, fluoromethyl, —CH₂—NH—C(═O)H

(Me represents a methyl group) etc.

Examples of another embodiment of a more preferable substituent in R²and R^(2a) include hydrogen, hydroxymethyl,methoxymethylcyclopropylmethyloxymethyl, aminomethyl, propyloxymethyl,etc.

Examples of another embodiment of a further preferable substituent in R²and R^(2a) include hydrogen.

Examples of a preferable substituent in R³ and R^(3a) include hydrogen,halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocycleoxy lower alkyl optionally substituted by substituentgroup C, heterocyclecarbonyl optionally substituted by substituent groupC, heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R¹)—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8))—Z—N(R^(C9))(R^(C10)), or—Z—SO₂—R^(C11)(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), RC¹⁰, R^(C11), and Z are as defined in item 13′or item 13)

Examples of a more preferable substituent in R³ and R^(3a) includehydrogen, lower alkyl optionally substituted by substituent group C,lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C,

—Z—N(R^(C1))—SO₂—R^(C2),—Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6),—Z—C(═O)—N(R^(C7))(R^(C8)), or—Z—N(R^(C9))(R^(C10))(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), R^(C10), and Z are as defined in item 13)

Examples of a further preferable substituent in R³ and R^(3a) includehydrogen, lower alkyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, or carbocycle loweralkyl optionally substituted by substituent group C

(substituent group C is as defined in item 13′ or item 13).

Examples of another embodiment of a preferable substituent in R³ andR^(3a) include hydrogen, ethoxyethyl, methyl, ethyl, propyl,2,4-difluorobenzyl, methoxyethyl, cyanomethyl, cyanoethyl,3-chloro-2-fluorobenzyl, 1-methoxypropyl, pyridylmethyl, isopropyl,tetrahydropyranylmethyl, cyclopropylmethyl, benzyl,methylisoxazolylmethyl, methyloxadiazolyl, isopropyloxyethyl,hydroxyethyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl,—CH(Me)CH₂OMe, carboxyethyl, —CH₂CH₂C(═O)—N(Me)₂, —CH₂CH₂N(Me)-S(═O)₂-Ph, —CH₂CH₂—N(Me)-S(═O)₂-Me, —CH₂CH₂—NHC(═O)-Ph, —CH(Me)-CH₂—OMe, —CH₂CH₂—NH—S(═O)₂-Ph, —CH₂CH₂—NH—C(═O)—O—CH (Me)₂,—CH₂CH₂—C(═O)—NH-Ph, —CH₂CH₂—N(Me)C(═O)-Ph, —CH₂CH₂—NH—C(═O)-Me,—CH₂CH₂—NH—S(═O)₂-Me, aminoethyl, —CH₂CH₂—N(Me)-C(═O)-Me,—CH₂CH₂—C(═O)—N(Me)-Ph, —CH₂CH₂—NH—C(═O)—O-tBu,piperidinylcarbonylethyl, dimethylaminoethyl, cyclopropylmethyl,methylaminoethyl, furanylmethyl, morpholinylcarbonylethyl, sec-butyl,pentan-2-yl, carboxypropyl, ethoxycarbonylpropyl, phenylpropyl,propyloxyethyl, aminopropyl, dimethylaminomethyl, dimethylaminoethyl,diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl,methylaminocarbonylethyl, 1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl,1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl, trifluoromethyloxyethyl,trifluoromethylcarbonylaminomethyl, methylsulfonylethyl,methylcarbonyloxyethyl, methylcarbonyloxypropyl, 1-fluoropropyl,fluorocyclopropyl, difluorocyclopropyl, 3,3-dimethylbutan-2-yl,1-fluoroethyl, 1-methoxypropan-2-yl, amino, thiazolylmethyl,methylsulfonylethyl, 4-fluorophenyloxyethyl, pyridyl, pentan-2-yl,butan-2-yl, 3-methylbuten-2-yl, as well as groups shown below:

(Me represents a methyl group, Ph represents a phenyl group, and tBurepresents a tert-butyl group) etc.

Examples of another embodiment of a more preferable substituent in R³and R^(3a) include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl,methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl,pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl,benzyl, methylisoxazolylmethyl, 4-fluorobenzyl, cyclopropyl,ethoxycarbonylethyl, —CH(Me)CH₂OMe, carboxyethyl, —CH₂CH₂C(═O)—N(Me)₂,—CH₂CH₂N(Me)-S(═O)₂-Ph, —CH₂CH₂—N(Me)-S(═O)₂-Me, —CH₂CH₂—NHC(═O)-Ph, —CH(Me)-CH₂—OMe, —CH₂CH₂—NH—S(═O)₂-Ph, —CH₂CH₂—NH—C(═O)—O—CH(Me)₂,—CH₂CH₂—C(═O)—NH-Ph, —CH₂CH₂—N(Me)C(═O)-Ph, —CH₂CH₂—NH—C(═O)-Me,—CH₂CH₂—NH—S(═O)₂-Me, aminoethyl, 1,1,1-trifluoropropan-2-yl, propyl,methylthiomethyl, hydrogen, fluorocyclopropyl, trifluoromethoxyethyl,1-fluoropropyl, 1-fluoroethyl, methylcarbonyloxymethyl,1,1-difluoromethyl, and groups shown below:

(Me represents methyl group, and Ph represents phenyl group) etc.

Examples of another embodiment of a further preferable substituent in R³and R^(3a) include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl,methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl,pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl,benzyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl, —CH(Me)CH₂OMe,carboxyethyl, 1,1,1-trifluoropropan-2-yl, hydroxyethyl, 1-fluoroethyl(Me represents methyl group) etc.

Examples of another embodiment of a most preferable substituent in R³and R^(3a) include 1,1,1-trifluoropropan-2-yl.

Examples of a preferable substituent in R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹as well R^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a), and R^(11a)include hydrogen, carboxy, cyano, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Y—S—R^(D1), —Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),—Z—C(R^(D7))(R^(D8))(R^(D9)), or—Z—CH₂—R^(D10)(substituent group C, R^(D1), R^(D2), R^(D3), R^(D4), R^(D5), R^(D6),R^(D7), R^(D8), R^(D9), R^(D10) and Z are as defined in item 13′ or item13).

Examples of a more preferable substituent in R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,and R¹¹, as well as R^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a), andR^(11a) include hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C,

—Y—S—R^(D1), or

—Z—C(R^(D7))(R^(D8))(R^(D9))(substituent group C, R^(D1), R^(D7), R^(D8), R^(D9), Y, and Z are asdefined in item 13′ or item 13).

Examples of another embodiment of a preferable substituent in R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, and R¹¹, as well as R^(5a), R^(6a), R^(7a), R^(8a),R^(9a), R^(10a), and R^(11a) include hydrogen, benzhydryl, benzyl,indolylmethyl, cyclohexylmethyl, phenethyl, benzylthiomethyl,3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl, 4-fluorobenzyl,methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl,3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl,pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, isobutyl,phenoxyethyl, methoxypropyl, phenylpropyl, as well as the followinggroups:

(wherein R^(E6) represents a group selected from substituent group A orsubstituent group C, and m of R^(E6)s may be the same or different) etc.

Examples of another embodiment of a more preferable substituent in R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹, as well as R^(5a), R^(6a), R^(7a), R^(8a),R^(9a), R^(10a), and R^(11a) include hydrogen, benzhydryl, benzyl,indolylmethyl, cyclohexylmethyl, phenethyl, 3,5-dimethylisoxazolyl,5-chloro-3-ethylbenzothiophenyl, biphenylmethyl, 4-fluorobenzyl,methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl,3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl,pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, and thefollowing groups:

(wherein R^(E6) represents a group selected from substituent group A orsubstituent group C, and m of R^(E6)s may be the same or different).etc.1) Examples of a preferable embodiment when A¹ is CR⁵R⁶, and A² is NR⁷include the case where R³ and R⁷ are taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupB.2) Examples of a preferable embodiment when A¹ is NR⁷, and A² is CR⁵R⁶include the case where R³ and R⁶ are taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupB.3) Examples of a preferable embodiment when A¹ is CR⁸R⁹, and A² isCR¹⁰R¹¹ include the case where R⁸ and R¹⁰ are taken together with anadjacent atom to form a carbocycle or a heterocycle optionallysubstituted by substituent group B.4) Examples of another preferable embodiment when A¹ is CR⁸R⁹, and A² isCR¹⁰R¹¹ include the case where R³ and R¹¹ are taken together with anadjacent atom to form a heterocycle optionally substituted bysubstituent group B.1) Examples of a preferable embodiment when B¹ is CR^(5a)R^(6a), and B²is NR^(7a) include the case where R^(3a) and R^(7a) are taken togetherwith an adjacent atom to form a heterocycle optionally substituted bysubstituent group D.2) Examples of a preferable embodiment when B¹ is NR^(7a), and B² isCR^(5a)R^(6a) include the case where R^(3a) and R^(6a) are takentogether with an adjacent atom to form a heterocycle optionallysubstituted by substituent group D.3) Examples of a preferable embodiment when B¹ is CR^(8a)R^(9a), and B²is CR^(10a)R^(11a) include the case where R^(8a) and R^(10a) are takentogether with an adjacent atom to form a carbocycle or a heterocycleoptionally substituted by substituent group D.4) Examples of another preferable embodiment when B¹ is CR^(8a)R^(9a),and B² is CR^(10a)R^(11a) include the case where R^(3a) and R^(11a) aretaken together with an adjacent atom to form a heterocycle optionallysubstituted by substituent group D.

When any one of A¹ and A² is CR⁵R⁶, and the other is NR⁷, the case whereA¹ is NR⁷, and A² is CR⁵R⁶ is more preferable.

When any one of B¹ and B² is CR^(5a)R^(6a), and the other is NR^(7a),the case where B¹ is NR^(7a), and B² is CR^(5a)R^(6a) is morepreferable.

When any one of A¹ and A² is CR⁵R⁶, and the other is NR⁷, it ispreferable that at least any one of R⁵ or R⁶ is hydrogen. A morepreferable embodiment is such that R⁵ is hydrogen, and R⁶ is hydrogen.In this case, R⁷ is not a hydrogen atom.

When any one of B¹ and B² is CR^(5a)R^(6a), and the other is NR^(7a), itis preferable that at least any one of R^(5a) or R^(6a) is hydrogen. Amore preferable embodiment is such that R^(5a) is hydrogen, and R^(6a)is hydrogen. In this case, R^(7a) is not a hydrogen atom.

A preferable embodiment of R⁷ and R^(7a) is carbocyclic group optionallysubstituted by substituent group A, carbocycle lower alkyl optionallysubstituted by substituent group A, heterocyclic group optionallysubstituted by substituent group A, and hetereocyclic lower alkyloptionally substituted by substituent group A.

A more preferable embodiment of R⁷ and R^(7a) is cycloalkyl,cycloalkenyl, aryl, non-aromatic condensed carbocyclic group,heteroaryl, non-aromatic heterocyclic group, bicyclic condensedheterocyclic group, tricyclic condensed heterocyclic group, lower alkylsubstituted by one or two carbocyclic groups, and lower alkylsubstituted by one or two heterocyclic groups.

A further preferable embodiment of R⁷ and R^(7a) is benzyl, benzhydryl,4-fluorobenzyl, p-methoxybenzyl, and the following groups:

(wherein R^(E6), and m are as defined in item 13′).

A most preferable embodiment of R⁷ and R^(7a) is the following groups:

(wherein R^(E6), and m are as defined in item 13′).

When A¹ is CR⁸R⁹, and A² is CR¹⁰R¹¹, it is preferable that R⁹ and R¹¹are hydrogen. A preferable embodiment of R⁸ and R¹⁰ is such that any oneof them is hydrogen.

When R⁹ and R¹¹ are hydrogen, and any one of R⁸ and R¹⁰ is hydrogen, apreferable embodiment of the other of R⁸ and R¹⁰ is carbocyclic groupoptionally substituted by substituent group A, carbocycle lower alkyloptionally substituted by substituent group A, heterocyclic groupoptionally substituted by substituent group A, and heterocycle loweralkyl optionally substituted by substituent group A.

When B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a), it is preferablethat R^(9a) and R^(11a) are hydrogen. A preferable embodiment of R^(8a)and R^(10a) is such that any one of them is hydrogen.

When R^(9a) and R^(11a) are hydrogen, and any one of R^(8a) and R^(10a)is hydrogen, a preferable embodiment of the other of R^(8a) and R^(10a)is the following groups

—Z—C(R^(E1))(R^(E2))(R^(E3))or

(wherein Z, R^(E1), R^(E2), R^(E3), R^(E6) and m are as defined in item13 or item 13′).

When R^(9a) and R^(11a) are hydrogen, and any one of R^(8a) and R^(10a)is hydrogen, a further preferable embodiment of the other of R^(8a) andR^(10a) is the following groups:

(wherein R^(E6) and m are as defined in item 13 or item 13′).

Examples of a preferable substituent in substituent group B andsubstituent group D include carbocyclic group optionally substituted bysubstituent group A or substituent group C, heterocyclic groupoptionally substituted by substituent group A or substituent group C,carbocycle lower alkyl optionally substituted by substituent group A orsubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group A or substituent group C.

Examples of another embodiment of a preferable substituent insubstituent group B and substituent group D include benzyl, benzhydryl,4-fluorobenzyl, p-methoxybenzyl,

(wherein R^(E6) represents a group selected from substituent group A orsubstituent group C, and m of R^(E6)s may be the same or different) etc.

Examples of a preferable substituent of R^(E6) include halogen, cyano,hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno loweralkyl, lower alkyloxy, halogeno lower alkyloxy, etc.

Examples of a more preferable substituent of R^(E6) include fluorineatom, chlorine atom, bromine atom, cyano, methyl, hydroxymethyl,isopropyl, methoxy, trifluoromethyl, oxo, carboxy, etc.

A preferable embodiment of m is an integer of 0 to 6, further preferablyan integer of 0 to 3, most preferably an integer of 0 to 2.

Examples of a preferable substituent of R^(1d) include hydrogen,halogen, lower alkyloxy optionally substituted by substituent group E,carbocycle lower alkyloxy optionally substituted by substituent group E,and —OSi(R^(1e))₃.

Examples of R^(1e)s each include independently lower alkyl optionallysubstituted by substituent group E, and carbocyclic group optionallysubstituted by substituent group E.

Examples of a preferable substituent of R^(2d) include lower alkyloptionally substituted by substituent group E.

Examples of a preferable embodiment of R^(3d) include —N(R^(3e))₂, or—OR^(3e).

R^(3e)s are each independently lower alkyl optionally substituted bysubstituent group E.

Examples of a preferable substituent of R^(4d) include lower alkyloptionally substituted by substituent group E, and carbocycle loweralkyl optionally substituted by substituent group E.

Examples of a preferable substituent of R^(5d) include halogen, andlower alkyloxy optionally substituted by substituent group E.

Examples of a preferable substituent of R^(6d) include lower alkyloptionally substituted by substituent group E, and lower alkenyloptionally substituted by substituent group E.

Examples of a preferable substituent of P^(d) include lower alkyloptionally substituted by substituent group E.

Examples of another embodiment of a preferable substituent of R^(1d)include hydrogen, chlorine atom, bromine atom, methoxy, ethoxy,tert-butyloxy, trifluoromethoxy, benzyloxy, p-methoxybenzyloxy,trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy,diisopropylsilyloxy, triphenylsilyloxy, etc.

Examples of another embodiment of a preferable substituent of R^(2d)include methyl, ethyl, isopropyl, tert-butyl, p-methoxybenzyl, andp-nitrobenzyl.

Examples of another embodiment of a preferable substituent of R^(3d)include methoxy, ethoxy, isopropyloxy, benzyloxy, —N(Me)₂, —N(Et)₂,—N(iPr)₂ (Me represents methyl group, Et represents ethyl group, and^(i)Pr represents isopropyl group) etc.

Examples of another embodiment of a preferable substituent of R^(4d)include methyl, ethyl, isopropyl, tert-butyl, p-methoxybenzyl, andp-nitrobenzyl, etc.

Examples of another embodiment of a preferable substituent of R^(5d)include hydrogen, chlorine atom, bromine atom, methoxy, ethoxy,tert-butyloxy, trifluoromethoxy, —O—SO₂—CH₃, —O—SO₂-Ph-CH₃ (Phrepresents phenyl group) etc.

Examples of another embodiment of a preferable substituent of R^(6d)include methyl, ethyl, isopropyl, allyl, —CH₂—CH(OMe)₂, —CH₂—CH(OEt)₂,

etc.

Examples of another embodiment of a preferable substituent of P^(d)include methyl, ethyl, isopropyl, etc.

One of characteristics of the compound in the present invention is inthat a polycyclic carbamoylpyridone derivative, in which two or morerings are condensed, such as shown in the formula (I) in item 1′ anditem 1 and/or the formula (II) in item 13′ and item 13 and/or acomposition including them, has high inhibitory activity oncap-dependent endonuclease.

Another characteristic of the compound in the present invention is thatcap-dependent endonuclease inhibitory activity was improved, by applyinga functional group as shown below to R¹ in the formula (I) and/or R^(1a)in the formula (II). Functional group: hydrogen, halogen, hydroxy,carboxy, cyano, formyl, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkyloxy optionally substituted by substituent group C, loweralkenyloxy optionally substituted by substituent group C, loweralkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxy optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A3))—SO₂—(R^(A4)),—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R^(A11),

—Z—N(R^(A12))—C(═O)—O—R^(A13),—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(substituent group C, R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8),R^(A9), R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17), R^(A18),R^(A19), R^(A20), and R^(A21) are as defined in item 13′ or item 13).

The characteristic of a more preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity isimproved, by applying a functionl group shown below to R¹ in the formula(I) and/or R^(1a) in the formula (II).

Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group A,—Z—N(R^(A1))(R^(A2)),—Z—N(R^(A7))—C(═O)—R^(A8), or—Z—N(R^(A12))—C(═O)—O—R^(A13)(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),and Z are as defined in item 13′ or item 13).

The characteristic of a further preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity isimproved, by applying a functional group shown below to R¹ in theformula (I) and/or R^(1a) in the formula (II).

Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group A, or—Z—N(R^(A1))(R^(A2))(substituent group C, R^(A1), R^(A2) and Z are as defined in item 13′ oritem 13).

The characteristic of a particularly preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity isimproved, by applying a functional group shown below to R¹ in theformula (I) and/or R^(1a) in the formula (II).

Functional group: hydrogen, or carboxy

Other characteristic of the compound in the present invention is thatcap-dependent endonuclease inhibitory activity was improved, byintroducing one, two or more of lipid-soluble functional groups shownbelow on carbon atom or on nitrogen atom of A¹ and/or A² in the formula(I), as well as of B¹ and/or B² in the formula (II).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C(substituent group C is as defined in item 13′ or item 13).

Other characteristic of a more preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity isimproved, by introducing one lipid-soluble functional group shown belowon carbon atom or on nitrogen atom of A¹ and/or A² in the formula (I),as well as of B¹ and/or B² in the formula (II).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C(substituent group C is as defined in item 13′ or item 13).

Other characteristic of a particularly preferable compound in thepresent invention is that cap-dependent endonuclease inhibitory activitywas improved, by introducing one lipid-soluble functional group shownbelow on carbon atom or on nitrogen atom of A¹ and/or A² in the formula(I), as well as of B¹ and/or B² in the formula (II).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C,(substituent group C is as defined in item 13′ or item 13).

A preferable embodiment of the present invention will be exemplifiedbelow.

In the formula (III), the formula (III′), the formula (III″), theformula (III′″), the formula (III″″), the formula (III′″″):

1)a compound in which R^(1b) is hydrogen (hereinafter, R^(1b) is R1-1), acompound in which R^(1b) is carboxy (hereinafter, R^(b) is R1-2) acompound in which R^(1b) is halogen (hereinafter R^(1b) is R1-3), acompound in which R^(1b) is hydroxy (hereinafter, R^(1b) is R1-4), acompound in which R^(1b) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(1b) is R1-5),a compound in which R^(1b) is lower alkylcarbonyl optionally substitutedby substituent group C (hereinafter, R^(1b) is R1-6),a compound in which R^(1b) is lower alkyloxycarbonyl optionallysubstituted by substituent group C (hereinafter, R^(1b) is R1-7),a compound in which R^(1b) is amino (hereinafter, R^(1b) is R1-8),2)a compound in which R^(2b) is hydrogen (hereinafter, R^(2b) is R2-1),a compound in which R^(2b) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(2b) is R2-2),3)a compound in which R^(3b) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(3b) is R3-1),a compound in which R^(3b) is carbocycle lower alkyl optionallysubstituted by substituent group C (hereinafter, R^(3b) is R3-2),a compound in which R^(3b) is heterocycle lower alkyl optionallysubstituted by substituent group C (hereinafter, R^(3b) is R3-3),a compound in which R^(3b) is carbocyclic group optionally substitutedby substituent group C (hereinafter, R^(3b) is R3-4),a compound in which R^(3b) is heterocyclic group optionally substitutedby substituent group C (hereinafter, R^(3b) is R3-5),in the formula (III′),1)a compound in which R^(7b) is carbocyclic group optionally substitutedby substituent group C, and R^(5b) and R^(6b) are hydrogen (hereinafter,R7-1),a compound in which R^(7b) is heterocyclic group optionally substitutedby substituent group C, and R^(5b) and R^(6b) are hydrogen (hereinafter,R7-2),a compound in which R^(7b) is carbocycle lower alkyl optionallysubstituted by substituent group C, and R^(5b) and R^(6b) are hydrogen(hereinafter, R7-3),2)a compound in which R^(6b) is carbocyclic group optionally substitutedby substituent group C, and R^(5b) and R^(7b) are hydrogen (hereinafter,R6-1),a compound in which R^(6b) is heterocyclic group optionally substitutedby substituent group C, and R^(5b) and R^(7b) are hydrogen (hereinafter,R6-2),a compound in which R^(6b) is carbocycle lower alkyl optionallysubstituted by substituent group C, and R^(5b) and R^(7b) are hydrogen(hereinafter, R6-3),in the formula (III),a compound in which R^(9b) is carbocyclic group optionally substitutedby substituent group C, and R^(8b), R^(10b) and R^(11b) are hydrogen(hereinafter, R9-1),a compound in which R^(9b) is heterocyclic group optionally substitutedby substituent group C, and R^(8b), R^(10b) and R^(11b) are hydrogen(hereinafter, R9-1),a compound in which R^(9b) is carbocycle lower alkyl optionallysubstituted by substituent group C, and R^(8b), R^(10b), and R^(11b) arehydrogen (hereinafter, R9-1).

Herein, the substituent group C is at least one selected from asubstituent group consisting of halogen, cyano, hydroxy, carboxy,formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, loweralkyloxy, carbocyclic group, heterocyclic group, carbocycle loweralkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, loweralkyloxy lower alkyl, lower alkyloxy lower alkyloxy, loweralkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, andlower alkylsulfonylamino.

Compounds in which, in the formula (III′), a combination of R^(1b),R^(2b), R^(3b), as well as (R^(5b), R^(6b), and R^(7b)) is as follows.

(R1-1, R2-1, R3-1, R7-1), (R1-1, R2-1, R3-1, R7-2), (R1-1, R2-1, R3-1,R7-3), (R1-1, R2-1, R3-2, R7-1), (R1-1, R2-1, R3-2, R7-2), (R1-1, R2-1,R3-2, R7-3), (R1-1, R2-1, R3-3, R7-1), (R1-1, R2-1, R3-3, R7-2), (R1-1,R2-1, R3-3, R7-3), (R1-1, R2-1, R3-4, R7-1), (R1-1, R2-1, R3-4, R7-2),(R1-1, R2-1, R3-4, R7-3), (R1-1, R2-1, R3-5, R7-1), (R1-1, R2-1, R3-5,R7-2), (R1-1, R2-1, R3-5, R7-3), (R1-1, R2-2, R3-1, R7-1), (R1-1, R2-2,R3-1, R7-2), (R1-1, R2-2, R3-1, R7-3), (R1-1, R2-2, R3-2, R7-1), (R1-1,R2-2, R3-2, R7-2), (R1-1, R2-2, R3-2, R7-3), (R1-1, R2-2, R3-3, R7-1),(R1-1, R2-2, R3-3, R7-2), (R1-1, R2-2, R3-3, R7-3), (R1-1, R2-2, R3-4,R7-1), (R1-1, R2-2, R3-4, R7-2), (R1-1, R2-2, R3-4, R7-3), (R1-1, R2-2,R3-5, R7-1), (R1-1, R2-2, R3-5, R7-2), (R1-1, R2-2, R3-5, R7-3), (R1-2,R2-1, R3-1, R7-1), (R1-2, R2-1, R3-1, R7-2), (R1-2, R2-1, R3-1, R7-3),(R1-2, R2-1, R3-2, R7-1), (R1-2, R2-1, R3-2, R7-2), (R1-2, R2-1, R3-2,R7-3), (R1-2, R2-1, R3-3, R7-1), (R1-2, R2-1, R3-3, R7-2), (R1-2, R2-1,R3-3, R7-3), (R1-2, R2-1, R3-4, R7-1), (R1-2, R2-1, R3-4, R7-2), (R1-2,R2-1, R3-4, R7-3), (R1-2, R2-1, R3-5, R7-1), (R1-2, R2-1, R3-5, R7-2),(R1-2, R2-1, R3-5, R7-3), (R1-2, R2-2, R3-1, R7-1), (R1-2, R2-2, R3-1,R7-2), (R1-2, R2-2, R3-1, R7-3), (R1-2, R2-2, R3-2, R7-1), (R1-2, R2-2,R3-2, R7-2), (R1-2, R2-2, R3-2, R7-3), (R1-2, R2-2, R3-3, R7-1), (R1-2,R2-2, R3-3, R7-2), (R1-2, R2-2, R3-3, R7-3), (R1-2, R2-2, R3-4, R7-1),(R1-2, R2-2, R3-4, R7-2), (R1-2, R2-2, R3-4, R7-3), (R1-2, R2-2, R3-5,R7-1), (R1-2, R2-2, R3-5, R7-2), (R1-2, R2-2, R3-5, R7-3), (R1-3, R2-1,R3-1, R7-1), (R1-3, R2-1, R3-1, R7-2), (R1-3, R2-1, R3-1, R7-3), (R1-3,R2-1, R3-2, R7-1), (R1-3, R2-1, R3-2, R7-2), (R1-3, R2-1, R3-2, R7-3),(R1-3, R2-1, R3-3, R7-1), (R1-3, R2-1, R3-3, R7-2), (R1-3, R2-1, R3-3,R7-3), (R1-3, R2-1, R3-4, R7-1), (R1-3, R2-1, R3-4, R7-2), (R1-3, R2-1,R3-4, R7-3), (R1-3, R2-1, R3-5, R7-1), (R1-3, R2-1, R3-5, R7-2), (R1-3,R2-1, R3-5, R7-3), (R1-3, R2-2, R3-1, R7-1), (R1-3, R2-2, R3-1, R7-2),(R1-3, R2-2, R3-1, R7-3), (R1-3, R2-2, R3-2, R7-1), (R1-3, R2-2, R3-2,R7-2), (R1-3, R2-2, R3-2, R7-3), (R1-3, R2-2, R3-3, R7-1), (R1-3, R2-2,R3-3, R7-2), (R1-3, R2-2, R3-3, R7-3), (R1-3, R2-2, R3-4, R7-1), (R1-3,R2-2, R3-4, R7-2), (R1-3, R2-2, R3-4, R7-3), (R1-3, R2-2, R3-5, R7-1),(R1-3, R2-2, R3-5, R7-2), (R1-3, R2-2, R3-5, R7-3), (R1-4, R2-1, R3-1,R7-1), (R1-4, R2-1, R3-1, R7-2), (R1-4, R2-1, R3-1, R7-3), (R1-4, R2-1,R3-2, R7-1), (R1-4, R2-1, R3-2, R7-2), (R1-4, R2-1, R3-2, R7-3), (R1-4,R2-1, R3-3, R7-1), (R1-4, R2-1, R3-3, R7-2), (R1-4, R2-1, R3-3, R7-3),(R1-4, R2-1, R3-4, R7-1), (R1-4, R2-1, R3-4, R7-2), (R1-4, R2-1, R3-4,R7-3), (R1-4, R2-1, R3-5, R7-1), (R1-4, R2-1, R3-5, R7-2), (R1-4, R2-1,R3-5, R7-3), (R1-4, R2-2, R3-1, R7-1), (R1-4, R2-2, R3-1, R7-2), (R1-4,R2-2, R3-1, R7-3), (R1-4, R2-2, R3-2, R7-1), (R1-4, R2-2, R3-2, R7-2),(R1-4, R2-2, R3-2, R7-3), (R1-4, R2-2, R3-3, R7-1), (R1-4, R2-2, R3-3,R7-2), (R1-4, R2-2, R3-3, R7-3), (R1-4, R2-2, R3-4, R7-1), (R1-4, R2-2,R3-4, R7-2), (R1-4, R2-2, R3-4, R7-3), (R1-4, R2-2, R3-5, R7-1), (R1-4,R2-2, R3-5, R7-2), (R1-4, R2-2, R3-5, R7-3),(R1-5, R2-1, R3-1, R7-1), (R1-5, R2-1, R3-1, R7-2), (R1-5, R2-1, R3-1,R7-3), (R1-5, R2-1, R3-2, R7-1), (R1-5, R2-1, R3-2, R7-2), (R1-5, R2-1,R3-2, R7-3), (R1-5, R2-1, R3-3, R7-1), (R1-5, R2-1, R3-3, R7-2), (R1-5,R2-1, R3-3, R7-3), (R1-5, R2-1, R3-4, R7-1), (R1-5, R2-1, R3-4, R7-2),(R1-5, R2-1, R3-4, R7-3), (R1-5, R2-1, R3-5, R7-1), (R1-5, R2-1, R3-5,R7-2), (R1-5, R2-1, R3-5, R7-3), (R1-5, R2-2, R3-1, R7-1), (R1-5, R2-2,R3-1, R7-2), (R1-5, R2-2, R3-1, R7-3), (R1-5, R2-2, R3-2, R7-1), (R1-5,R2-2, R3-2, R7-2), (R1-5, R2-2, R3-2, R7-3), (R1-5, R2-2, R3-3, R7-1),(R1-5, R2-2, R3-3, R7-2), (R1-5, R2-2, R3-3, R7-3), (R1-5, R2-2, R3-4,R7-1), (R1-5, R2-2, R3-4, R7-2), (R1-5, R2-2, R3-4, R7-3), (R1-5, R2-2,R3-5, R7-1), (R1-5, R2-2, R3-5, R7-2), (R1-5, R2-2, R3-5, R7-3), (R1-6,R2-1, R3-1, R7-1), (R1-6, R2-1, R3-1, R7-2), (R1-6, R2-1, R3-1, R7-3),(R1-6, R2-1, R3-2, R7-1), (R1-6, R2-1, R3-2, R7-2), (R1-6, R2-1, R3-2,R7-3), (R1-6, R2-1, R3-3, R7-1), (R1-6, R2-1, R3-3, R7-2), (R1-6, R2-1,R3-3, R7-3), (R1-6, R2-1, R3-4, R7-1), (R1-6, R2-1, R3-4, R7-2), (R1-6,R2-1, R3-4, R7-3), (R1-6, R2-1, R3-5, R7-1), (R1-6, R2-1, R3-5, R7-2),(R1-6, R2-1, R3-5, R7-3), (R1-6, R2-2, R3-1, R7-1), (R1-6, R2-2, R3-1,R7-2), (R1-6, R2-2, R3-1, R7-3), (R1-6, R2-2, R3-2, R7-1), (R1-6, R2-2,R3-2, R7-2), (R1-6, R2-2, R3-2, R7-3), (R1-6, R2-2, R3-3, R7-1), (R1-6,R2-2, R3-3, R7-2), (R1-6, R2-2, R3-3, R7-3), (R1-6, R2-2, R3-4, R7-1),(R1-6, R2-2, R3-4, R7-2), (R1-6, R2-2, R3-4, R7-3), (R1-6, R2-2, R3-5,R7-1), (R1-6, R2-2, R3-5, R7-2), (R1-6, R2-2, R3-5, R7-3), (R1-7, R2-1,R3-1, R7-1), (R1-7, R2-1, R3-1, R7-2), (R1-7, R2-1, R3-1, R7-3), (R1-7,R2-1, R3-2, R7-1), (R1-7, R2-1, R3-2, R7-2), (R1-7, R2-1, R3-2, R7-3),(R1-7, R2-1, R3-3, R7-1), (R1-7, R2-1, R3-3, R7-2), (R1-7, R2-1, R3-3,R7-3), (R1-7, R2-1, R3-4, R7-1), (R1-7, R2-1, R3-4, R7-2), (R1-7, R2-1,R3-4, R7-3), (R1-7, R2-1, R3-5, R7-1), (R1-7, R2-1, R3-5, R7-2), (R1-7,R2-1, R3-5, R7-3), (R1-7, R2-2, R3-1, R7-1), (R1-7, R2-2, R3-1, R7-2),(R1-7, R2-2, R3-1, R7-3), (R1-7, R2-2, R3-2, R7-1), (R1-7, R2-2, R3-2,R7-2), (R1-7, R2-2, R3-2, R7-3), (R1-7, R2-2, R3-3, R7-1), (R1-7, R2-2,R3-3, R7-2), (R1-7, R2-2, R3-3, R7-3), (R1-7, R2-2, R3-4, R7-1), (R1-7,R2-2, R3-4, R7-2), (R1-7, R2-2, R3-4, R7-3), (R1-7, R2-2, R3-5, R7-1),(R1-7, R2-2, R3-5, R7-2), (R1-7, R2-2, R3-5, R7-3), (R1-8, R2-1, R3-1,R7-1), (R1-8, R2-1, R3-1, R7-2), (R1-8, R2-1, R3-1, R7-3), (R1-8, R2-1,R3-2, R7-1), (R1-8, R2-1, R3-2, R7-2), (R1-8, R2-1, R3-2, R7-3), (R1-8,R2-1, R3-3, R7-1), (R1-8, R2-1, R3-3, R7-2), (R1-8, R2-1, R3-3, R7-3),(R1-8, R2-1, R3-4, R7-1), (R1-8, R2-1, R3-4, R7-2), (R1-8, R2-1, R3-4,R7-3), (R1-8, R2-1, R3-5, R7-1), (R1-8, R2-1, R3-5, R7-2), (R1-8, R2-1,R3-5, R7-3), (R1-8, R2-2, R3-1, R7-1), (R1-8, R2-2, R3-1, R7-2), (R1-8,R2-2, R3-1, R7-3), (R1-8, R2-2, R3-2, R7-1), (R1-8, R2-2, R3-2, R7-2),(R1-8, R2-2, R3-2, R7-3), (R1-8, R2-2, R3-3, R7-1), (R1-8, R2-2, R3-3,R7-2), (R1-8, R2-2, R3-3, R7-3), (R1-8, R2-2, R3-4, R7-1), (R1-8, R2-2,R3-4, R7-2), (R1-8, R2-2, R3-4, R7-3), (R1-8, R2-2, R3-5, R7-1), (R1-8,R2-2, R3-5, R7-2), (R1-8, R2-2, R3-5, R7-3),(R1-1, R2-1, R3-1, R6-1), (R1-1, R2-1, R3-1, R6-2), (R1-1, R2-1, R3-1,R6-3), (R1-1, R2-1, R3-2, R6-1), (R1-1, R2-1, R3-2, R6-2), (R1-1, R2-1,R3-2, R6-3), (R1-1, R2-1, R3-3, R6-1), (R1-1, R2-1, R3-3, R6-2), (R1-1,R2-1, R3-3, R6-3), (R1-1, R2-1, R3-4, R6-1), (R1-1, R2-1, R3-4, R6-2),(R1-1, R2-1, R3-4, R6-3), (R1-1, R2-1, R3-5, R6-1), (R1-1, R2-1, R3-5,R6-2), (R1-1, R2-1, R3-5, R6-3), (R1-1, R2-2, R3-1, R6-1), (R1-1, R2-2,R3-1, R6-2), (R1-1, R2-2, R3-1, R6-3), (R1-1, R2-2, R3-2, R6-1), (R1-1,R2-2, R3-2, R6-2), (R1-1, R2-2, R3-2, R6-3), (R1-1, R2-2, R3-3, R6-1),(R1-1, R2-2, R3-3, R6-2), (R1-1, R2-2, R3-3, R6-3), (R1-1, R2-2, R3-4,R6-1), (R1-1, R2-2, R3-4, R6-2), (R1-1, R2-2, R3-4, R6-3), (R1-1, R2-2,R3-5, R6-1), (R1-1, R2-2, R3-5, R6-2), (R1-1, R2-2, R3-5, R6-3), (R1-2,R2-1, R3-1, R6-1), (R1-2, R2-1, R3-1, R6-2), (R1-2, R2-1, R3-1, R6-3),(R1-2, R2-1, R3-2, R6-1), (R1-2, R2-1, R3-2, R6-2), (R1-2, R2-1, R3-2,R6-3), (R1-2, R2-1, R3-3, R6-1), (R1-2, R2-1, R3-3, R6-2), (R1-2, R2-1,R3-3, R6-3), (R1-2, R2-1, R3-4, R6-1), (R1-2, R2-1, R3-4, R6-2), (R1-2,R2-1, R3-4, R6-3), (R1-2, R2-1, R3-5, R6-1), (R1-2, R2-1, R3-5, R6-2),(R1-2, R2-1, R3-5, R6-3), (R1-2, R2-2, R3-1, R6-1), (R1-2, R2-2, R3-1,R6-2), (R1-2, R2-2, R3-1, R6-3), (R1-2, R2-2, R3-2, R6-1), (R1-2, R2-2,R3-2, R6-2), (R1-2, R2-2, R3-2, R6-3), (R1-2, R2-2, R3-3, R6-1), (R1-2,R2-2, R3-3, R6-2), (R1-2, R2-2, R3-3, R6-3), (R1-2, R2-2, R3-4, R6-1),(R1-2, R2-2, R3-4, R6-2), (R1-2, R2-2, R3-4, R6-3), (R1-2, R2-2, R3-5,R6-1), (R1-2, R2-2, R3-5, R6-2), (R1-2, R2-2, R3-5, R6-3), (R1-3, R2-1,R3-1, R6-1), (R1-3, R2-1, R3-1, R6-2), (R1-3, R2-1, R3-1, R6-3), (R1-3,R2-1, R3-2, R6-1), (R1-3, R2-1, R3-2, R6-2), (R1-3, R2-1, R3-2, R6-3),(R1-3, R2-1, R3-3, R6-1), (R1-3, R2-1, R3-3, R6-2), (R1-3, R2-1, R3-3,R6-3), (R1-3, R2-1, R3-4, R6-1), (R1-3, R2-1, R3-4, R6-2), (R1-3, R2-1,R3-4, R6-3), (R1-3, R2-1, R3-5, R6-1), (R1-3, R2-1, R3-5, R6-2), (R1-3,R2-1, R3-5, R6-3), (R1-3, R2-2, R3-1, R6-1), (R1-3, R2-2, R3-1, R6-2),(R1-3, R2-2, R3-1, R6-3), (R1-3, R2-2, R3-2, R6-1), (R1-3, R2-2, R3-2,R6-2), (R1-3, R2-2, R3-2, R6-3), (R1-3, R2-2, R3-3, R6-1), (R1-3, R2-2,R3-3, R6-2), (R1-3, R2-2, R3-3, R6-3), (R1-3, R2-2, R3-4, R6-1), (R1-3,R2-2, R3-4, R6-2), (R1-3, R2-2, R3-4, R6-3), (R1-3, R2-2, R3-5, R6-1),(R1-3, R2-2, R3-5, R6-2), (R1-3, R2-2, R3-5, R6-3), (R1-4, R2-1, R3-1,R6-1), (R1-4, R2-1, R3-1, R6-2), (R1-4, R2-1, R3-1, R6-3), (R1-4, R2-1,R3-2, R6-1), (R1-4, R2-1, R3-2, R6-2), (R1-4, R2-1, R3-2, R6-3), (R1-4,R2-1, R3-3, R6-1), (R1-4, R2-1, R3-3, R6-2), (R1-4, R2-1, R3-3, R6-3),(R1-4, R2-1, R3-4, R6-1), (R1-4, R2-1, R3-4, R6-2), (R1-4, R2-1, R3-4,R6-3), (R1-4, R2-1, R3-5, R6-1), (R1-4, R2-1, R3-5, R6-2), (R1-4, R2-1,R3-5, R6-3), (R1-4, R2-2, R3-1, R6-1), (R1-4, R2-2, R3-1, R6-2), (R1-4,R2-2, R3-1, R6-3), (R1-4, R2-2, R3-2, R6-1), (R1-4, R2-2, R3-2, R6-2),(R1-4, R2-2, R3-2, R6-3), (R1-4, R2-2, R3-3, R6-1), (R1-4, R2-2, R3-3,R6-2), (R1-4, R2-2, R3-3, R6-3), (R1-4, R2-2, R3-4, R6-1), (R1-4, R2-2,R3-4, R6-2), (R1-4, R2-2, R3-4, R6-3), (R1-4, R2-2, R3-5, R6-1), (R1-4,R2-2, R3-5, R6-2), (R1-4, R2-2, R3-5, R6-3),(R1-5, R2-1, R3-1, R6-1), (R1-5, R2-1, R3-1, R6-2), (R1-5, R2-1, R3-1,R6-3), (R1-5, R2-1, R3-2, R6-1), (R1-5, R2-1, R3-2, R6-2), (R1-5, R2-1,R3-2, R6-3), (R1-5, R2-1, R3-3, R6-1), (R1-5, R2-1, R3-3, R6-2), (R1-5,R2-1, R3-3, R6-3), (R1-5, R2-1, R3-4, R6-1), (R1-5, R2-1, R3-4, R6-2),(R1-5, R2-1, R3-4, R6-3), (R1-5, R2-1, R3-5, R6-1), (R1-5, R2-1, R3-5,R6-2), (R1-5, R2-1, R3-5, R6-3), (R1-5, R2-2, R3-1, R6-1), (R1-5, R2-2,R3-1, R6-2), (R1-5, R2-2, R3-1, R6-3), (R1-5, R2-2, R3-2, R6-1), (R1-5,R2-2, R3-2, R6-2), (R1-5, R2-2, R3-2, R6-3), (R1-5, R2-2, R3-3, R6-1),(R1-5, R2-2, R3-3, R6-2), (R1-5, R2-2, R3-3, R6-3), (R1-5, R2-2, R3-4,R6-1), (R1-5, R2-2, R3-4, R6-2), (R1-5, R2-2, R3-4, R6-3), (R1-5, R2-2,R3-5, R6-1), (R1-5, R2-2, R3-5, R6-2), (R1-5, R2-2, R3-5, R6-3), (R1-6,R2-1, R3-1, R6-1), (R1-6, R2-1, R3-1, R6-2), (R1-6, R2-1, R3-1, R6-3),(R1-6, R2-1, R3-2, R6-1), (R1-6, R2-1, R3-2, R6-2), (R1-6, R2-1, R3-2,R6-3), (R1-6, R2-1, R3-3, R6-1), (R1-6, R2-1, R3-3, R6-2), (R1-6, R2-1,R3-3, R6-3), (R1-6, R2-1, R3-4, R6-1), (R1-6, R2-1, R3-4, R6-2), (R1-6,R2-1, R3-4, R6-3), (R1-6, R2-1, R3-5, R6-1), (R1-6, R2-1, R3-5, R6-2),(R1-6, R2-1, R3-5, R6-3), (R1-6, R2-2, R3-1, R6-1), (R1-6, R2-2, R3-1,R6-2), (R1-6, R2-2, R3-1, R6-3), (R1-6, R2-2, R3-2, R6-1), (R1-6, R2-2,R3-2, R6-2), (R1-6, R2-2, R3-2, R6-3), (R1-6, R2-2, R3-3, R6-1), (R1-6,R2-2, R3-3, R6-2), (R1-6, R2-2, R3-3, R6-3), (R1-6, R2-2, R3-4, R6-1),(R1-6, R2-2, R3-4, R6-2), (R1-6, R2-2, R3-4, R6-3), (R1-6, R2-2, R3-5,R6-1), (R1-6, R2-2, R3-5, R6-2), (R1-6, R2-2, R3-5, R6-3), (R1-7, R2-1,R3-1, R6-1), (R1-7, R2-1, R3-1, R6-2), (R1-7, R2-1, R3-1, R6-3), (R1-7,R2-1, R3-2, R6-1), (R1-7, R2-1, R3-2, R6-2), (R1-7, R2-1, R3-2, R6-3),(R1-7, R2-1, R3-3, R6-1), (R1-7, R2-1, R3-3, R6-2), (R1-7, R2-1, R3-3,R6-3), (R1-7, R2-1, R3-4, R6-1), (R1-7, R2-1, R3-4, R6-2), (R1-7, R2-1,R3-4, R6-3), (R1-7, R2-1, R3-5, R6-1), (R1-7, R2-1, R3-5, R6-2), (R1-7,R2-1, R3-5, R6-3), (R1-7, R2-2, R3-1, R6-1), (R1-7, R2-2, R3-1, R6-2),(R1-7, R2-2, R3-1, R6-3), (R1-7, R2-2, R3-2, R6-1), (R1-7, R2-2, R3-2,R6-2), (R1-7, R2-2, R3-2, R6-3), (R1-7, R2-2, R3-3, R6-1), (R1-7, R2-2,R3-3, R6-2), (R1-7, R2-2, R3-3, R6-3), (R1-7, R2-2, R3-4, R6-1), (R1-7,R2-2, R3-4, R6-2), (R1-7, R2-2, R3-4, R6-3), (R1-7, R2-2, R3-5, R6-1),(R1-7, R2-2, R3-5, R6-2), (R1-7, R2-2, R3-5, R6-3), (R1-8, R2-1, R3-1,R6-1), (R1-8, R2-1, R3-1, R6-2), (R1-8, R2-1, R3-1, R6-3), (R1-8, R2-1,R3-2, R6-1), (R1-8, R2-1, R3-2, R6-2), (R1-8, R2-1, R3-2, R6-3), (R1-8,R2-1, R3-3, R6-1), (R1-8, R2-1, R3-3, R6-2), (R1-8, R2-1, R3-3, R6-3),(R1-8, R2-1, R3-4, R6-1), (R1-8, R2-1, R3-4, R6-2), (R1-8, R2-1, R3-4,R6-3), (R1-8, R2-1, R3-5, R6-1), (R1-8, R2-1, R3-5, R6-2), (R1-8, R2-1,R3-5, R6-3), (R1-8, R2-2, R3-1, R6-1), (R1-8, R2-2, R3-1, R6-2), (R1-8,R2-2, R3-1, R6-3), (R1-8, R2-2, R3-2, R6-1), (R1-8, R2-2, R3-2, R6-2),(R1-8, R2-2, R3-2, R6-3), (R1-8, R2-2, R3-3, R6-1), (R1-8, R2-2, R3-3,R6-2), (R1-8, R2-2, R3-3, R6-3), (R1-8, R2-2, R3-4, R6-1), (R1-8, R2-2,R3-4, R6-2), (R1-8, R2-2, R3-4, R6-3), (R1-8, R2-2, R3-5, R6-1), (R1-8,R2-2, R3-5, R6-2), (R1-8, R2-2, R3-5, R6-3).Compounds in which, in the formula (III), a combination of R^(1b),R^(2b), R^(3b), as well as (R^(8b), R^(9b), R^(10b), and R^(11b)) is asfollows.(R1-1, R2-1, R3-1, R9-1), (R1-1, R2-1, R3-1, R9-2), (R1-1, R2-1, R3-1,R9-3), (R1-1, R2-1, R3-2, R9-1), (R1-1, R2-1, R3-2, R9-2), (R1-1, R2-1,R3-2, R9-3), (R1-1, R2-1, R3-3, R9-1), (R1-1, R2-1, R3-3, R9-2), (R1-1,R2-1, R3-3, R9-3), (R1-1, R2-1, R3-4, R9-1), (R1-1, R2-1, R3-4, R9-2),(R1-1, R2-1, R3-4, R9-3), (R1-1, R2-1, R3-5, R9-1), (R1-1, R2-1, R3-5,R9-2), (R1-1, R2-1, R3-5, R9-3), (R1-1, R2-2, R3-1, R9-1), (R1-1, R2-2,R3-1, R9-2), (R1-1, R2-2, R3-1, R9-3), (R1-1, R2-2, R3-2, R9-1), (R1-1,R2-2, R3-2, R9-2), (R1-1, R2-2, R3-2, R9-3), (R1-1, R2-2, R3-3, R9-1),(R1-1, R2-2, R3-3, R9-2), (R1-1, R2-2, R3-3, R9-3), (R1-1, R2-2, R3-4,R9-1), (R1-1, R2-2, R3-4, R9-2), (R1-1, R2-2, R3-4, R9-3), (R1-1, R2-2,R3-5, R9-1), (R1-1, R2-2, R3-5, R9-2), (R1-1, R2-2, R3-5, R9-3), (R1-2,R2-1, R3-1, R9-1), (R1-2, R2-1, R3-1, R9-2), (R1-2, R2-1, R3-1, R9-3),(R1-2, R2-1, R3-2, R9-1), (R1-2, R2-1, R3-2, R9-2), (R1-2, R2-1, R3-2,R9-3), (R1-2, R2-1, R3-3, R9-1), (R1-2, R2-1, R3-3, R9-2), (R1-2, R2-1,R3-3, R9-3), (R1-2, R2-1, R3-4, R9-1), (R1-2, R2-1, R3-4, R9-2), (R1-2,R2-1, R3-4, R9-3), (R1-2, R2-1, R3-5, R9-1), (R1-2, R2-1, R3-5, R9-2),(R1-2, R2-1, R3-5, R9-3), (R1-2, R2-2, R3-1, R9-1), (R1-2, R2-2, R3-1,R9-2), (R1-2, R2-2, R3-1, R9-3), (R1-2, R2-2, R3-2, R9-1), (R1-2, R2-2,R3-2, R9-2), (R1-2, R2-2, R3-2, R9-3), (R1-2, R2-2, R3-3, R9-1), (R1-2,R2-2, R3-3, R9-2), (R1-2, R2-2, R3-3, R9-3), (R1-2, R2-2, R3-4, R9-1),(R1-2, R2-2, R3-4, R9-2), (R1-2, R2-2, R3-4, R9-3), (R1-2, R2-2, R3-5,R9-1), (R1-2, R2-2, R3-5, R9-2), (R1-2, R2-2, R3-5, R9-3), (R1-3, R2-1,R3-1, R9-1), (R1-3, R2-1, R3-1, R9-2), (R1-3, R2-1, R3-1, R9-3), (R1-3,R2-1, R3-2, R9-1), (R1-3, R2-1, R3-2, R9-2), (R1-3, R2-1, R3-2, R9-3),(R1-3, R2-1, R3-3, R9-1), (R1-3, R2-1, R3-3, R9-2), (R1-3, R2-1, R3-3,R9-3), (R1-3, R2-1, R3-4, R9-1), (R1-3, R2-1, R3-4, R9-2), (R1-3, R2-1,R3-4, R9-3), (R1-3, R2-1, R3-5, R9-1), (R1-3, R2-1, R3-5, R9-2), (R1-3,R2-1, R3-5, R9-3), (R1-3, R2-2, R3-1, R9-1), (R1-3, R2-2, R3-1, R9-2),(R1-3, R2-2, R3-1, R9-3), (R1-3, R2-2, R3-2, R9-1), (R1-3, R2-2, R3-2,R9-2), (R1-3, R2-2, R3-2, R9-3), (R1-3, R2-2, R3-3, R9-1), (R1-3, R2-2,R3-3, R9-2), (R1-3, R2-2, R3-3, R9-3), (R1-3, R2-2, R3-4, R9-1), (R1-3,R2-2, R3-4, R9-2), (R1-3, R2-2, R3-4, R9-3), (R1-3, R2-2, R3-5, R9-1),(R1-3, R2-2, R3-5, R9-2), (R1-3, R2-2, R3-5, R9-3), (R1-4, R2-1, R3-1,R9-1), (R1-4, R2-1, R3-1, R9-2), (R1-4, R2-1, R3-1, R9-3), (R1-4, R2-1,R3-2, R9-1), (R1-4, R2-1, R3-2, R9-2), (R1-4, R2-1, R3-2, R9-3), (R1-4,R2-1, R3-3, R9-1), (R1-4, R2-1, R3-3, R9-2), (R1-4, R2-1, R3-3, R9-3),(R1-4, R2-1, R3-4, R9-1), (R1-4, R2-1, R3-4, R9-2), (R1-4, R2-1, R3-4,R9-3), (R1-4, R2-1, R3-5, R9-1), (R1-4, R2-1, R3-5, R9-2), (R1-4, R2-1,R3-5, R9-3), (R1-4, R2-2, R3-1, R9-1), (R1-4, R2-2, R3-1, R9-2), (R1-4,R2-2, R3-1, R9-3), (R1-4, R2-2, R3-2, R9-1), (R1-4, R2-2, R3-2, R9-2),(R1-4, R2-2, R3-2, R9-3), (R1-4, R2-2, R3-3, R9-1), (R1-4, R2-2, R3-3,R9-2), (R1-4, R2-2, R3-3, R9-3), (R1-4, R2-2, R3-4, R9-1), (R1-4, R2-2,R3-4, R9-2), (R1-4, R2-2, R3-4, R9-3), (R1-4, R2-2, R3-5, R9-1), (R1-4,R2-2, R3-5, R9-2), (R1-4, R2-2, R3-5, R9-3),(R1-5, R2-1, R3-1, R9-1), (R1-5, R2-1, R3-1, R9-2), (R1-5, R2-1, R3-1,R9-3), (R1-5, R2-1, R3-2, R9-1), (R1-5, R2-1, R3-2, R9-2), (R1-5, R2-1,R3-2, R9-3), (R1-5, R2-1, R3-3, R9-1), (R1-5, R2-1, R3-3, R9-2), (R1-5,R2-1, R3-3, R9-3), (R1-5, R2-1, R3-4, R9-1), (R1-5, R2-1, R3-4, R9-2),(R1-5, R2-1, R3-4, R9-3), (R1-5, R2-1, R3-5, R9-1), (R1-5, R2-1, R3-5,R9-2), (R1-5, R2-1, R3-5, R9-3), (R1-5, R2-2, R3-1, R9-1), (R1-5, R2-2,R3-1, R9-2), (R1-5, R2-2, R3-1, R9-3), (R1-5, R2-2, R3-2, R9-1), (R1-5,R2-2, R3-2, R9-2), (R1-5, R2-2, R3-2, R9-3), (R1-5, R2-2, R3-3, R9-1),(R1-5, R2-2, R3-3, R9-2), (R1-5, R2-2, R3-3, R9-3), (R1-5, R2-2, R3-4,R9-1), (R1-5, R2-2, R3-4, R9-2), (R1-5, R2-2, R3-4, R9-3), (R1-5, R2-2,R3-5, R9-1), (R1-5, R2-2, R3-5, R9-2), (R1-5, R2-2, R3-5, R9-3), (R1-6,R2-1, R3-1, R9-1), (R1-6, R2-1, R3-1, R9-2), (R1-6, R2-1, R3-1, R9-3),(R1-6, R2-1, R3-2, R9-1), (R1-6, R2-1, R3-2, R9-2), (R1-6, R2-1, R3-2,R9-3), (R1-6, R2-1, R3-3, R9-1), (R1-6, R2-1, R3-3, R9-2), (R1-6, R2-1,R3-3, R9-3), (R1-6, R2-1, R3-4, R9-1), (R1-6, R2-1, R3-4, R9-2), (R1-6,R2-1, R3-4, R9-3), (R1-6, R2-1, R3-5, R9-1), (R1-6, R2-1, R3-5, R9-2),(R1-6, R2-1, R3-5, R9-3), (R1-6, R2-2, R3-1, R9-1), (R1-6, R2-2, R3-1,R9-2), (R1-6, R2-2, R3-1, R9-3), (R1-6, R2-2, R3-2, R9-1), (R1-6, R2-2,R3-2, R9-2), (R1-6, R2-2, R3-2, R9-3), (R1-6, R2-2, R3-3, R9-1), (R1-6,R2-2, R3-3, R9-2), (R1-6, R2-2, R3-3, R9-3), (R1-6, R2-2, R3-4, R9-1),(R1-6, R2-2, R3-4, R9-2), (R1-6, R2-2, R3-4, R9-3), (R1-6, R2-2, R3-5,R9-1), (R1-6, R2-2, R3-5, R9-2), (R1-6, R2-2, R3-5, R9-3), (R1-7, R2-1,R3-1, R9-1), (R1-7, R2-1, R3-1, R9-2), (R1-7, R2-1, R3-1, R9-3), (R1-7,R2-1, R3-2, R9-1), (R1-7, R2-1, R3-2, R9-2), (R1-7, R2-1, R3-2, R9-3),(R1-7, R2-1, R3-3, R9-1), (R1-7, R2-1, R3-3, R9-2), (R1-7, R2-1, R3-3,R9-3), (R1-7, R2-1, R3-4, R9-1), (R1-7, R2-1, R3-4, R9-2), (R1-7, R2-1,R3-4, R9-3), (R1-7, R2-1, R3-5, R9-1), (R1-7, R2-1, R3-5, R9-2), (R1-7,R2-1, R3-5, R9-3), (R1-7, R2-2, R3-1, R9-1), (R1-7, R2-2, R3-1, R9-2),(R1-7, R2-2, R3-1, R9-3), (R1-7, R2-2, R3-2, R9-1), (R1-7, R2-2, R3-2,R9-2), (R1-7, R2-2, R3-2, R9-3), (R1-7, R2-2, R3-3, R9-1), (R1-7, R2-2,R3-3, R9-2), (R1-7, R2-2, R3-3, R9-3), (R1-7, R2-2, R3-4, R9-1), (R1-7,R2-2, R3-4, R9-2), (R1-7, R2-2, R3-4, R9-3), (R1-7, R2-2, R3-5, R9-1),(R1-7, R2-2, R3-5, R9-2), (R1-7, R2-2, R3-5, R9-3), (R1-8, R2-1, R3-1,R9-1), (R1-8, R2-1, R3-1, R9-2), (R1-8, R2-1, R3-1, R9-3), (R1-8, R2-1,R3-2, R9-1), (R1-8, R2-1, R3-2, R9-2), (R1-8, R2-1, R3-2, R9-3), (R1-8,R2-1, R3-3, R9-1), (R1-8, R2-1, R3-3, R9-2), (R1-8, R2-1, R3-3, R9-3),(R1-8, R2-1, R3-4, R9-1), (R1-8, R2-1, R3-4, R9-2), (R1-8, R2-1, R3-4,R9-3), (R1-8, R2-1, R3-5, R9-1), (R1-8, R2-1, R3-5, R9-2), (R1-8, R2-1,R3-5, R9-3), (R1-8, R2-2, R3-1, R9-1), (R1-8, R2-2, R3-1, R9-2), (R1-8,R2-2, R3-1, R9-3), (R1-8, R2-2, R3-2, R9-1), (R1-8, R2-2, R3-2, R9-2),(R1-8, R2-2, R3-2, R9-3), (R1-8, R2-2, R3-3, R9-1), (R1-8, R2-2, R3-3,R9-2), (R1-8, R2-2, R3-3, R9-3), (R1-8, R2-2, R3-4, R9-1), (R1-8, R2-2,R3-4, R9-2), (R1-8, R2-2, R3-4, R9-3), (R1-8, R2-2, R3-5, R9-1), (R1-8,R2-2, R3-5, R9-2), (R1-8, R2-2, R3-5, R9-3).

Method for Producing Compound of the Present Invention

A general method for producing the compound of the present inventionwill be exemplified below. And, as extraction and purification,treatment which is performed in a normal experiment of organic chemistrymay be conducted.

Synthesis of the compound of the present invention can be carried outreferring to the procedures known in the art.

As a raw material compound, commercially available compounds, compoundsdescribed in the present description, compounds described in thereferences cited in the present description, and other known compoundscan be utilized.

Among the compounds of the present invention, there are compounds inwhich a tautomer can be present, and the present invention includes allpossible isomers and a mixture thereof, including them.

When one wants to obtain a salt of the compound of the presentinvention, in the case where the compound of the present invention isobtained in a form of a salt, it may be purified as it is and, in thecase where the compound of the present invention is obtained in a freeform, a salt may be formed by a normal method by dissolving orsuspending the compound in a suitable organic solvent, and adding anacid or a base.

In addition, the compound of the present invention and apharmaceutically acceptable salt thereof are present in a form ofadducts with water or various solvents (hydrate or solvate) in somecases, and these adducts are included in the present invention.

In a general synthesis method as well as Examples and ReferenceExamples, the meaning of each abbreviation is as follows.

DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide, NMP:N-methylpyrrolidone

DMI: dimethylimidazolidinoneTHF: tetrahydrofuranMs: methanesulfonylTs: paratoluenesulfonylBoc: tert-butoxycarbonylDIBALH: diisobutylaluminum hydrideWSC or EDCI: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimideHOBt: 1-hydroxybenzotriazoleHATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NBS: N-bromosuccinimide NCS: N-chlorosuccinimide

TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl radicalPDC: pyridinium dichloromateDEAD: diethyl azodicarboxylateDIAD: diisopropyl azodicarboxylateDMAP: 4-dimethylaminopyridinemCPBA: m-chloroperbenzoic acidDBU: 1,8-diazabicyclo[5.4.0]-7-undeceneDIPEA: diisopropylethylamineTBAF: tetrabutylammonium fluorideIBX: 2-iodoxybenzoic acidDMSO: dimethyl sulfoxideNaHMDS: sodium hexamethyldisilazideTFA: trifluoroacetic acid

Synthesis of Objective Compound aj (See: Example 1)

(wherein R is carboxy protective group, P¹ is hydroxyl protective group,R², R³, R⁸, R⁹, R and R¹¹ are as defined in item 1′ or item 1, R and P¹may be a group which can be protected and/or deprotected by the methoddescribed in Protective Groups in Organic Synthesis, Theodora W Green(John Wiley & Sons) etc. and, for example, R is lower alkyl etc., and P¹is arylalkyl etc.)

First Step

A compound ab can be obtained by reacting a compound aa which iscommercially available or can be prepared by the known method at −20° C.to 30° C., preferably 0° C. to 20° C. for 0.1 hour to 24 hours,preferably 0.5 hour to 12 hours in a solvent such as dichloromethane,toluene, THF etc. or a mixed solvent thereof, by adding dropwisetertiary amine such as pyridine, trimethylamine, N-methylmorpholine,4-dimethylaminopyridine etc. and benzyloxyacetyl chloride.

Second Step

A compound ac can be obtained by adding an organometallic base such aslithium hexamethyldisilazane, lithium diisopropylamide, butyllithium,tert-butyllithium etc. to the compound ab in a solvent such as ether,dichloromethane, THF etc. or a mixed solvent thereof, in the presence ofcinnamoyl chloride, and performing a reaction at −80° C. to 0° C.,preferably −80° C. to −40° C. for 1 minute to 2 hours, preferably 10minutes to 1 hour.

Third Step

A compound ad can be obtained by adding a catalytic amount of anoxidizing agent such as ruthenium chloride and sodium periodate, TEMPO,manganese dioxide, as well as PDC etc. to the compound ac in a solventsuch as ether, dichloromethane, THF, acetonitrile etc. or a mixedsolvent thereof, and performing a reaction at −40° C. to 80° C.,preferably 0° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.2 hourto 3 hours.

Fourth Step

Concentrated sulfuric acid and an aqeuous solution of amidosuluflic acidare added to the compound ad at 0° C. to 60° C., preferably 10° C. to40° C. in the presence of a solvent such as ether, dichloromethane, THF,acetonitrile, acetone, water etc. or in a mixed solvent thereof. Anaqueous sodium chlorite solution is added dropwise thereto at the sametemperature to perform a reaction for 1 minute to 3 hours, preferably 5minutes to 1 hour, thereby, a compound ae can be obtained.

Fifth Step

A compound af can be obtained by adding a compound R³—NH₂ having asubstituent corresponding to an objective compound to the compound ae ina solvent such as DMF, THF, dichloromethane, acetonitrile etc. in thepresence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5,-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATUetc., and performing a reaction at −20° C. to 60° C., preferably −10° C.to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound ah can be obtained by adding a compound ag to the compound afin the presence of a solvent such as toluene, xylene, THF, dioxane etc.or in a mixed solvent thereof, and performing a reaction for 0.1 hour to12 hours, preferably 0.2 hour to 6 hours under the heat-refluxingcondition.

Seventh Step

A compound ai can be obtained by adding triphenylphosphine and acondensation agent such as DEAD, DIAD etc. to the compound ah in thepresence of a solvent such as THF, dioxane, ethyl acetate, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 12 hours,preferably 0.2 hour to 6 hours.

Eighth Step

By subjecting the compound ai to the known general deprotecting reactionof a carboxyl protective group and a hydroxyl protective group, acompound aj can be obtained.

Synthesis of Compound bk (See: Example 12)

(wherein P² is amino protective group, P² may be a group which can beprotected and/or deprotected by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.and, for example, P² is arylalkyloxycarbonyl, lower alkyloxycarbonyl,etc. Other each symbol is as defined above)

First Step

A compound bb can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, cesium carbonate etc. and a compound P²-L(wherein L is a leaving group such as halogen, OMs etc.) having asubstituent corresponding to an objective compound to a compound ba inthe presence of a solvent such as DMF, THF, dioxane, acetonitrile etc.or in a mixed solvent thereof, and performing a reaction at −20° C. to80° C., preferably 0° C. to 50° C. for 0.1 hour to 6 hours, preferably0.2 hour to 6 hours.

Second Step

A compound bc can be obtained by adding triphenylphosphine andphthalimide to the compound bb in the presence of a solvent such as DMF,THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding adehydration-condensation reagent such as DIAD, DEAD etc., and performinga reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1 hourto 24 hours, preferably 0.2 hour to 12 hours.

Third Step

A compound bd can be obtained by adding hydrazine hydrate ormethylhydrazine to the compound bc in the presence of a solvent such asmethanol, THF, dioxane, acetonitrile, etc. or in a mixed solventthereof, and performing a reaction at −10° C. to 80° C., preferably 10°C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12 hours.

Fourth Step

A compound be can be obtained by adding Boc₂O to the compound bd in thepresence of a solvent such as THF, dioxane, acetonitrile etc. or in amixed solvent thereof, and performing a reaction at −10° C. to 80° C.,preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12hours.

Fifth Step

A compound bf can be obtained by subjecting the compound be to the knowngeneral deprotecting reaction of an amino protective group.

Sixth Step

A compound bh can be obtained by adding a compound bg to the compound bfin the presence of a solvent such as toluene, THF, dioxane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 20° C.to 110° C., preferably 40° C. to under heat-refluxing for 0.5 hour to 24hours, preferably 1 hour to 12 hours.

Seventh Step

HCl-ethyl acetate, HCl-dioxane, formic acid etc. is added to thecompound bh, and they are reacted at 0° C. to 40° C., preferably 0° C.to 20° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours. Afterthe solvent is distilled off under reduced pressure, an aqueoussaturated sodium bicarbonate solution is added, and the mixture isstirred, thereby, a compound bi can be obtained.

Eighth Step

A compound bj can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and a compound R³-L (L is a leaving group such as halogen, OMs etc.) tothe compound bi in the presence of a solvent such as DMF, THF, DMA, NMPetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 60° C., preferably 10° C. to 30° C. for 0.5 hour to 12 hours,preferably 1 hour to 6 hours.

Ninth Step

A compound bk can be obtained by subjecting the compound bj to the knowngeneral deprotecting reaction of a carboxyl protective group and ahydroxyl protective group.

Synthesis of Compound cd (See: Examples 28 and 43)

(wherein each symbol is as defined above)

First Step

A compound cb can be obtained by adding tertiary amine such astriethylamine, DMAP, morpholine etc. or a base such as sodium carbonate,sodium bicarbonate etc. to a compound ca in the presence of a solventsuch as THF, dioxane, acetonitrile, water etc. or in a mixed solventthereof, adding Boc₂O, and performing a reaction at −10° C. to 80° C.,preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12hours.

Second Step

A compound cc can be obtained by adding triphenylphosphine andphthalimide to the compound cb in the presence of a solvent such as DMF,THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding adehydration-condensation reagent such as DIAD, DEAD etc., and performinga reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1 hourto 24 hours, preferably 0.2 hour to 12 hours.

Third Step

A compound cd can be obtained by adding hydrazine hydrate to thecompound cc in the presence of a solvent such as methanol, THF, dioxane,acetonitrile etc. or in a mixed solvent thereof, and performing areaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hourto 24 hours, preferably 1 to 12 hours.

Synthesis of Compound dg (See: Examples 36, 41 and 46)

(wherein B¹ and B² are as defined in item 13′ or item 13, and other eachsymbol is as defined above).

First Step

A compound db can be obtained by subjecting the compound da obtained bythe same method as the synthesis method of bi to the known generalcarboxyl deprotecting reaction.

Second Step

A decarbonized compound dc can be obtained by reacting the compound dbfor 1 minute to 2 hours under microwave irradiation in a solvent such asdiphenyl ether etc. And, a decarbonized compound dc can be obtained byadding copper in a quinoline solvent, and performing a reaction at 180°C. for 2 to 48 hours.

Third Step

A compound dd can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and a compound R³-L (L is a leaving group such as halogen, OMs etc.) tothe compound da obtained by the method described in Example 12 in thepresence of a solvent such as DMF, THF, DMA, NMP etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hourto 6 hours.

Fourth Step

A compound de can be obtained by the same method as that of the firststep.

Fifth Step

A compound df can be obtained by the same method as that of the secondstep.

Sixth Step

A compound df can be obtained by the same method as that of the thirdstep.

Seventh Step

A compound dg can be obtained by subjecting the compound df to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound ec (See: Example 48)

(wherein each symbol is as defined above)

First Step

A base such as triethylamine, N-methylmorpholine, diisopropylethylamineetc. and ethyl chloroformate are added to a compound ea in the presenceof a solvent such as THF, dioxane, dichloromethane, toluene etc. or in amixed solvent thereof. A reducing agent having a low reducing power suchas sodium borohydride etc. is added thereto, and a reaction is performedat −20° C. to 60° C., preferably −10° C. to 20° C. for 0.2 hour to 12hours, preferably 0.5 hour to 6 hours, thereby, a compound eb can beobtained.

Second Step

A compound ec can be obtained by subjecting the compound eb to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound fh (See: Example 50)

(wherein each symbol is as defined above)

First Step

A compound fb and triphenylphosphine are added to a compound fa in thepresence of a solvent such as THF, dichloromethane, dioxane,acetonitrile etc. or in a mixed solvent thereof. DIAD is added thereto,and a reaction is performed at 0° C. to 60° C., preferably 10° C. to 30°C. for 0.5 hour to 12 hours, preferably 1 hour to 12 hours, thereby, acompound fc can be obtained.

Second Step

A compound fd can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and thiol such as benzenethiol etc. to the compound fc in the presenceof a solvent such as THF, dioxane, acetonitrile etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hourto 12 hours.

Third Step

A compound ff can be obtained by adding a compound fe having asubstituent corresponding to an objective compound to the compound fd ina solvent such as DMF, THF, dichloromethane, acetonitrile etc. in thepresence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl etc.,and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40°C. for 1 hour to 48 hours, preferably 2 hours to 24 hours.

Fourth Step

A compound fg can be obtained by subjecting the compound ff to the knowngeneral deprotecting reaction concerning a P² group on an amino group,subsequently, adding a base such as an aqueous sodium carbonatesolution, an aqueous potassium carbonate solution etc. in a solvent suchas water, ethanol, methanol, acetonitrile etc. or in a mixed solventthereof, and performing a reaction at 20° C. to 80° C., preferably 20°C. to 70° C. for 0.5 hour to 24 hours, preferably 1 hour to 6 hours.

Fifth Step

A compound fh can be obtained by subjecting the compound fd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound ga (See: Example 51)

(wherein each symbol is as defined above)

First Step

A compound ga can be obtained by subjecting a compound dd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound hh (See: Example 52)

(wherein each symbol is as defined above)

First Step

A compound hb can be obtained by adding O,N-dimethylhydroxylaminehydrochloride to a compound ha in a solvent such as DMF, THF,dichloromethane, acetonitrile etc. in the presence of adehydration-condensation agent such as dicyclohexylcarbodiimide,carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATUetc., adding a tertiary base such as triethylamine,diisopropylethylamine, N-methylmorpholine etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 1 hour to24 hours, preferably 1 hour to 12 hours.

Second Step

A compound he can be obtained by adding a Grignard reagent (R—MgBr) tothe compound hb at −80° C. to −40° C. in the presence of a solvent suchas THF, ether, dichloromethane, dioxane etc. or in a mixed solventthereof, and performing a reaction at −80° C. to 0° C., preferably −60°C. to −20° C. for 0.5 hour to 24 hours, preferably 0.5 hour to 6 hours.

Third Step

A compound hd can be obtained by adding mCPBA to the compound he in thepresence of a solvent such as chloroform and dichloromethane, andperforming a reaction at −20° C. to 30° C., preferably 10° C. to 30° C.for 0.1 hour to 12 hours, preferably 0.5 hour to 6 hours.

Fourth Step

A compound he can be obtained by adding an aqueous sodium hydroxidesolution to the compound hd in the presence of a solvent such as ethanoletc., and performing a reaction at 0° C. to 120° C., preferably 30° C.to 90° C. for 1 minute to 10 hours, preferably 30 minutes to 120minutes.

Fifth Step

A compound hf can be obtained by subjecting the compound he to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound hg can be obtained by adding a compound R—Br etc.corresponding to an objective compound to a compound he in the presenceof a solvent such as chloroform, dichloromethane, THF, toluene etc. orin a mixed solvent thereof, adding a metal base such as sodium hydride,sodium methylate, n-butyllithium etc., and performing a reaction at −20°C. to 120° C., preferably 0° C. to 30° C. for 0.5 hour to 12 hours,preferably 1 hour to 6 hours.

Seventh Step

A compound hh can be obtained by subjecting the compound hg to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound ic (See: Example 53)

First Step

Tertiary amine such as triethylamine, diisopropylethylamine,N-methylmorpholine etc., and a chlorinating reagent such as ethylchlorocarbonate, and ethyl chloroformate are added to a compound ia inthe presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixedsolvent thereof, and the mixture is stirred at 0° C. to 30° C. for 0.1hour to 1 hour. A compound R—SO₂—NH₂ (e.g.: methanesulfonylamide)corresponding to an objective substance and DMAP are added thereto, anda reaction is performed at 40° C. to 100° C., preferably 40° C. to 80°C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours, thereby, acompound ib can be obtained.

Second Step

A compound ic can be obtained by subjecting the compound ib to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound je (See: Example 54)

(wherein each symbol is as defined above)

First Step

Tertiary amine such as triethylamine, N-methylmorpholine,diisopropylethylamine etc. and ethyl chloroformate or ethylchlorocarbonate are added to a compound ja in the presence of a solventsuch as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixedsolvent thereof. A reducing agent having low reactivity such as sodiumborohydride etc. is added thereto, and a reaction is performed at −20°C. to 40° C., preferably −10° C. to 20° C. for 0.2 hour to 12 hours,preferably 0.5 hour to 6 hours to obtain an alcohol intermediate. Thisintermediate is dissolved in dichloromethane, chloroform, etc., anoxidizing agent such as TEMPO, manganese dioxide, PDC etc. is added, anda reaction is performed at −40° C. to 30° C., preferably 0° C. to 30° C.for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours, thereby, acompound jb can be obtained.

Second Step

A compound jc can be obtained by adding 28% aqueous ammonia and iodineto the compound jb in the presence of a solvent such as THF, dioxane,dichloromethane etc., and performing a reaction at 0° C. to 40° C.,preferably 10° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hourto 6 hours.

Third Step

A compound jd can be obtained by adding sodium azide, and tertiary aminesuch as triethylamine, diisopropylethylamine, N-methylmorpholine etc. tothe compound jc in the presence of a solvent such as toluene, xylene,THF, dioxane etc. or in a mixed solvent thereof, and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.5 hour to24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound je can be obtained by subjecting the compound jd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compounds kd and kf (See: Example 56 and DerivativeThereof)

(wherein R^(m) is lower alkyl, R is a substituent corresponding to anobjective compound, W is —C(═O)— or —SO₂—, and other each symbol is asdefined above)

First Step

Tertiary amine such as triethylamine, N-methylmorpholine,diisopropylethylamine etc. and ethyl chloroformate or ethylchlorocarbonate are added to a compound ka in the presence of a solventsuch as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixedsolvent thereof. Sodium azide is added thereto to perform a reaction at0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours,preferably 1 hour to 12 hours. Thereafter, an alcohol (R^(m)—OH) isadded, and a reaction is performed at 20° C. to 60° C., preferably 20°C. to 50° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours,thereby, a compound kb can be obtained.

Second Step

A compound kc can be obtained by adding a base such as an aqueous sodiumhydroxide solution, an aqueous potassium hydroxide solution etc. to thecompound kb in a solvent such as ethanol, methanol, water etc. or in amixed solvent thereof, and performing a reaction at 20° C. to 80° C.,preferably 40° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 hourto 12 hours.

Third Step

A compound kd can be obtained by subjecting the compound kc to the knowngeneral hydroxyl group deprotecting reaction.

Fourth Step

A compound ke can be obtained by adding acid chloride (R—CO—Cl) orsulfonyl chloride (R—SO₂—Cl) corresponding to an objective substance toa compound kc in a solvent such as THF, dioxane, toluene,dichloromethane etc., adding tertiary amine such as pyridine,triethylamine, N-methylmorpholine etc. as necessary, and performing areaction at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hourto 12 hours, preferably 0.2 hour to 6 hours.

Fifth Step

A compound kf can be obtained by subjecting the compound ke to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound lc (See: Example 60)

(wherein R is a substituent corresponding to an objective compound, andother each symbol is as defined above)

First Step

Sodium hydride is added to a compound la in a solvent such as THF,dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMsetc.) corresponding to an objective substance is added thereto, and areaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C.for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours, thereby, acompound 1b can be obtained.

Alternatively, a compound 1b can be obtained by adding formaldehyde to acompound la in a solvent of formic acid, and performing a reaction at70° C. to 110° C. for 0.5 hour to 24 hours, preferably 1 hour to 12hours.

Second Step

A compound lc can be obtained by subjecting the compound lb to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound md (See: Example 61)

(wherein R is a substituent corresponding to an objective compound, andother each symbol is as defined above)

First Step

An amino-protected body mb can be obtained by adding Boc₂O etc. to acompound ma in a solvent such as THF, dioxane, acetonitrile, water etc.or in a mixed solvent thereof, and subjecting this to an amineprotecting reaction.

Second Step

Sodium hydride is added to a compound mb in a solvent such as THF,dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMsetc.) corresponding to an objective substance is added thereto, and areaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C.for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours, thereby, acompound mc can be obtained.

Third Step

A compound md can be obtained by subjecting the compound mc to the knowngeneral amino group and hydroxyl group deprotecting reaction.

Synthesis of Compound nc and Compound ne (See: Examples 63 and 64)

(wherein X is halogen, M is boronic acid ester such as B(O-phenyl)₃etc., and other each symbol is as defined above)

First Step

A compound nb can be obtained by adding a halogenating reagent (e.g.NBS, NCS, bromine etc.) to a compound na in a solvent such asdichloromethane, toluene, THF, dioxane etc., and performing a reactionfor 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours under theoverheating refluxing condition.

Second Step

A compound nc can be obtained by subjecting the compound nb to the knowngeneral hydroxyl group deprotecting reaction.

Third Step

Boronic acid ester (R-M) corresponding to an objective substance isadded to a compound nb in a solvent such as toluene, THF, DMF etc. or ina mixed solvent thereof, and a base such as potassium carbonate, sodiumcarbonate, sodium hydroxide etc. is added. A 0-valent palladium catalyst(e.g.: Pd(PPh₃)₄) is added thereto under nitrogen stream, and a reactionis performed at 60° C. to 120° C., preferably 80° C. to 110° C. for 1hour to 48 hours, preferably 2 hours to 24 hours, thereby, a compound ndcan be obtained.

Fourth Step

A compound ne can be obtained by subjecting the compound nd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound oh (See: Example 65)

(wherein R is a carboxyl protective group such as lower alkyl etc., R⁷is as defined in item 1′ or item 1, L¹ is a leaving group such ashalogen, OMs, OTs etc., and other symbol is as defined above)

First Step

A compound ob can be obtained by adding sodium chlorite andamidosulfuric acid to a compound oa in the presence of a solvent such asTHF, dioxane, dichloromethane, acetonitrile etc., and performing areaction at 0° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to24 hours, preferably 1 hour to 12 hours.

Second Step

A compound oc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to the compound ob in the presence of a solvent suchas DMF, DMA, NMP, THF etc., adding amine (R³—NH₂) corresponding to anobjective substance, and tertiary amine such as triethylamine,N-methylmorpholine, pyridine etc., and performing a reaction at 10° C.to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours,preferably 1 hour to 12 hours.

Third Step

A compound od can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound oc inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound oe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound od in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc., and performing a reaction at 60° C. to 120° C.,preferably 80° C. to 110° C. for 0.1 hour to 24 hours, preferably 1 hourto 12 hours.

Fifth Step

A compound of can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound oe in thepresence of a solvent such as DMF, DMA, NMP, THF etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound og can be obtained by subjecting the compound of to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound oh can be obtained by subjecting the compound og to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound pg (See: Example 95)

(wherein each symbol is as defined above)

First Step

A compound pb can be obtained by adding aqueous ammonia to a compoundpa, and performing a reaction at 0° C. to 30° C., preferably 10° C. to30° C. for 0.5 hour to 48 hours, preferably 1 hour to 24 hours.

Second Step

A compound pc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to the compound pb in the presence of a solvent suchas DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, adding amine(R³—NH₂) corresponding to an objective substance and, if necessary,tertiary amine such as triethylamine, N-methylmorpholine etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Third Step

A compound pd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound pc inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound pd in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc., and performing a reaction at 60° C. to 120° C.,preferably 80° C. to 110° C. for 0.1 hour to 12 hours, preferably 0.2hour to 6 hours.

Fifth Step

A compound pf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound pe in thepresence of a solvent such as DMF, DMA, NMP, THF etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound pg can be obtained by subjecting the compound pf to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound qg, Compound qi, and Compound qk (See: Example128)

(wherein R represents a carboxyl protective group, n represents aninteger of 0 to 6, R^(Z7) and R^(Z8) are as defined in item 1′ or item1, and other each symbol is as defined above)

First Step

A compound qc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound qa in the presence of a solvent such aspyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, addinga compound qb and, if necessary, tertiary amine such as triethylamine,N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hourto 12 hours.

Second Step

A compound qd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qc inthe presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixedsolvent thereof, and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hourto 24 hours.

Third Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound qd in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc. or in a mixed solvent thereof, and performing a reactionat 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 12hours, preferably 0.2 hour to 6 hours.

Alternatively, a compound qe can be obtained by performing a reaction at100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiationcondition in a solvent such as ethanol, isopropyl alcohol etc.

Fourth Step

A compound qf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound qe in thepresence of a solvent such as DMF, DMA, NMP etc. or in a mixed solventthereof, and performing a reaction at 0° C. to 60° C., preferably 10° C.to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.

Fifth Step

A compound qg can be obtained by subjecting the compound qf to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound qh can be obtained by subjecting the compound qf to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound qi can be obtained by subjecting the compound qh to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A compound qj can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound qh in the presence of a solvent such aspyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, addinga compound HNR^(Z7)R^(Z8) and, if necessary, tertiary amine such astriethylamine, diisopropylethylamine, N-methylmorpholine etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Ninth Step

A compound qk can be obtained by subjecting the compound qj to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound qq, Compound qs, Compound qu, and Compound qw(See: Example 128)

(wherein R^(Z2), R^(Z4), R^(Z9), R^(Z10), and R^(Z13) are as defined initem 1′ or item 1, and other each symbol is as defined above)

Step 1

A compound qm can be obtained by adding a condensation agent such asHATU, WSC.HCl, etc. to a compound qa in the presence of a solvent suchas pyridine, DMF, DMA, NMP etc. or in a mixed solvent thereof, adding acompound ql and, if necessary, tertiary amine such as triethylamine,diisopropylethylamine, N-methylmorpholine, etc., and performing areaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hourto 24 hours, preferably 1 hour to 12 hours.

Second Step

A compound qn can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qm inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.

Third Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound qn in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc. or in a mixed solvent thereof, and performing a reactionat 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 12hours, preferably 0.2 hour to 6 hours.

Alternatively, a compound qo can be obtained by performing a reaction at100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiationcondition in a solvent such as ethanol etc.

Fourth Step

A compound qp can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate, etc. to the compound qo in thepresence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hourto 24 hours.

Fifth Step

A compound qq can be obtained by subjecting the compound qp to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound qr can be obtained by subjecting the compound qp to the knowngeneral amino group deprotecting reaction.

Seventh Step

A compound qs can be obtained by subjecting the compound qr to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A compound qt can be obtained by adding a compound R^(Z10)-L¹corresponding to an objective substance, and a base such as sodiumcarbonate, potassium carbonate, cesium carbonate, etc. to the compoundqr in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in asolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hourto 24 hours.

Ninth Step

A compound qu can be obtained by subjecting the compound qt to the knowngeneral hydroxyl group deprotecting reaction.

Tenth Step

A base such as sodium carbonate, potassium carbonate, cesium carbonateetc. is added to the compound qr in the presence of a solvent such asTHF, dioxane, dichloromethane, acetonitrile, etc. A compound(R^(Z4)COCl, R^(Z2)SO₂Cl, or R^(Z13)OCOCl) corresponding to an objectivesubstance is added thereto, and a reaction is performed at −20° C. to60° C., preferably 0° C. to 30° C. for 0.1 hour to 48 hours, preferably1 hour to 24 hours, thereby, a compound qv can be obtained.

Eleventh Step

A compound qw can be obtained by subjecting the compound qv to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound rb (See: Example 155)

(wherein each symbol is as defined above)

A compound rb can be obtained by adding a compound R³NH₂ having asubstituent corresponding to an objective compound to a compound ra inthe presence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile,etc. or in a mixed solvent thereof, and performing a reaction at −20° C.to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours,preferably 1 hour to 12 hours.

Alternatively, a compound rb can be obtained by adding an acylatingreagent such as diphenylchlorophosphate, thionyl chloride, oxalylchloride, etc. to a compound ra in the presence or absence of a basesuch as pyridine, triethylamine, diisopropylethylamine,1-methylimidazole, etc. in the presence of a solent such as THF,dioxane, dichloromethane, DMF, etc. to generate acid chloride, adding acompound R³—NH₂ having a substituent corresponding to an objectivecompound, and performing a reaction at −20° C. to 60° C., preferably−10° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12hours.

Synthesis of Compound sl (See: Example 49)

(wherein P³ is an amino protective group, and may be a group which canbe protected and/or deprotected by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.and, for example, P³ is aryl lower alkyloxycarbonyl, loweralkylcarbonyl, etc. B is as defined in item 1′ or item 1, and other eachsymbol is as defined above.)

First Step

A compound sb can be obtained by adding an oxidizing reagent such asDess Martin Periodinane, manganese dioxide, PDC, etc, to a compound sain the presence of a solvent such as dichloromethane, THF, dioxane,toluene etc., and performing a reaction at −20° C. to 60° C., preferably0° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12hours.

Second Step

A compound sd can be obtained by adding sodium sulfate and anaminoalcohol sc corresponding to an objective substance to the compoundsb in the presence or absence of a solvent such as toluene, THF etc.,and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60°C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.

Third Step

A compound se can be obtained by subjecting the compound sd to the knowngeneral amino group deprotecting reaction.

Fourth Step

A compound sg can be obtained by adding a compound sf to the compound sein the presence of a solvent such as toluene, THF, dioxane etc., andperforming a reaction at 40° C. to 110° C., preferably 60° C. to 100° C.for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.

Fifth Step

A compound sh can be obtained by subjecting the compound sg to the knowngeneral amino group deprotecting reaction and, thereafter, performing areaction at 40° C. to 110° C., preferably 60° C. to 100° C. for 0.1 hourto 12 hours, preferably 0.2 hour to 6 hours in the presence of a solventsuch as toluene, THF, dioxane, etc.

Sixth Step

A compound si can be obtained by subjecting the compound sh to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound sj can be obtained by subjecting the compound si to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A decarbonized compound sk can be obtained by reacting the compound sifor 1 minute to 2 hours under microwave irradiation in a solvent such asdiphenyl ether etc.

Ninth Step

A compound sl can be obtained by subjecting the compound sk to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound un (See: Example 177)

(wherein L¹ represents a leaving group such as halogen, OMs, OTs etc.,and other each symbol is as defined above)

First Step

A compound ub can be obtained by subjecting a compound ua to a secondaryamino group protecting reaction.

Second Step

A compound uc can be obtained by subjecting the compound ub to a generalamino group protecting reaction.

Third Step

A compound ue can be obtained by adding a compound R⁷-L¹ correspondingto an objective compound to the compound uc in the presence of a solventsuch as DMF, DMA, NMP, etc. and a base such as NaH etc., and performinga reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hourto 12 hours, preferably 1 hour to 6 hours.

Fourth Step, Fifth step(wherein R³ and R⁷ may be bound adjacently and, in this case, a fourthstep and a fifth step are performed simultaneously).

A compound ue can be obtained by reacting a compound ud sequentiallywith compounds corresponding to an objective compound, R³-L¹ and R⁷-L¹in the presence of a solvent such as DMF, DMA, NMP etc. and a base suchas NaH etc.

Sixth Step

A compound ug can be obtained by subjecting a compound uf to a secondaryamino group protecting reaction.

Seventh Step

A compound uh can be obtained by subjecting the compound ug to asecondary amino group protecting reaction.

Eighth Step

A compound ue can be obtained by adding a base such as NaH etc. to thecompound uh in the presence of a solvent such as DMF, DMA, NMP,acetonitrile etc. or in a mixed solvent thereof, and performing areaction with a compound R³-L¹ corresponding to an objective compound.

Ninth Step

A compound uj can be obtained by subjecting the compound ue to a generalsecondary amine deprotecting reaction.

Tenth Step

A compound ul can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound uk in the presence of a solvent such asDMF, DMA, THF, etc., adding amine uj corresponding to an objectivesubstance, and tertiary amine such as pyridine, triethylamine,N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hourto 12 hours.

Eleventh Step

A compound um can be obtained by subjecting the compound ul to a generalamino group protecting reaction.

Twelfth Step

A compound un can be obtained by adding R⁵—C(═O)—R⁶, tertiary amine suchas, triethylamine, diisopropylethylamine, N-methylmorpholine, etc. tothe compound um in the presence of a solvent such as toluene, DMF, DMA,NMP etc., and performing a reaction at 60° C. to 120° C., preferably 80°C. to 100° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

Synthesis of Compound te

(wherein R′ may be a group which can be protected and/or deprotected bythe method described in Protective Groups in Organic Synthesis, TheodoraW Green (John Wiley & Sons) etc. and, for example, R′ is lower alkyletc. X is halogen, and other each symbol is as defined above.)

First Step

An alcohol (P¹—OH) corresponding to an objective substance is added toan organometallic base such as sodium tert-pentoxide, n-butyllithium,tert-butyllithium etc. in a solvent such as THF, ether, dichloromethane,DMI, DMF, DMA, etc. or in a mixed solution thereof. A solution of acompound ta is added dropwise thereto, and a reaction is performed at−20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 12 hours,preferably 0.5 hour to 6 hours, thereby, a compound tb can be obtained.

Second Step

A compound tc can be obtained by addingN,N-dimethylformamidodimethylacetal to the compound tb in a solvent suchas THF, dioxane, toluene, ethyl acetate etc. or in a mixed solventthereof, or without a solvent, and performing a reaction at 0° C. to 80°C., preferably 20° C. to 40° C. for 0.5 hour to 24 hours, preferably 1hour to 12 hours.

Third Step

A compound td corresponding to an objective substance is added to anorganometallic base such as sodium tert-pentoxide, n-butyllithium,tert-butyllithium, sodium methoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide etc. in a solvent such as THF,ether, DMI, methanol, ethanol, etc. or in a mixed solvent thereof. Asolution of the compound tc is added dropwise thereto, a reaction isperformed at −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hourto 24 hours, preferably 1 hour to 12 hours and, thereafter, an acid suchas hydrochloric acid, sulfuric acid etc. is added to perform a reactionat −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hour to 24hours, preferably 1 hour to 12 hours, thereby, a compound te can beobtained.

Synthesis of Compound tm and Compound tp (See: Examples 165, and 169)

(wherein R^(P) may be an acetal protective group which can protectand/or can be deprotected by the method described in Protective Groupsin Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, forexample, R^(P) is lower alkyl etc. Other each symbol is as definedabove.)

First Step

A compound th can be obtained by adding allylamine to a compound tfwhich can be synthesized by the same method as that of a compound te inthe presence of a solvent such as ethanol, THF, dioxane, acetonitrile,etc. or in a mixed solvent thereof, and performing a reaction at 0θ° C.to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 48 hours,preferably 1 hour to 24 hours.

Second Step

A compound ti can be obtained by adding a compound tg to a compound tfin the presence of a solvent such as ethanol, THF, dioxane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 48 hours,preferably 1 hour to 24 hours.

Third Step

A compound tj can be obtained by adding potassium osmate dihydrate,sodium periodate, and water to the compound th in the presence of asolvent such as THF, ethyl acetate, dioxane, etc. or in a mixed solventthereof, and performing a reaction at 0° C. to 60° C., preferably 10° C.to 40° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.

Alternatively, a compound tj can be obtained by introducing ozone intothe compound th at −10° C. to 20° C. in the presence of a solvent suchas THF, ethyl acetate, dioxane etc. or in a mixed solvent thereof and,subsequent to completion of the reaction, adding zinc-acetic acid,(EtO)₃P, or dimethyl sulfide.

Fourth Step

A compound tk can be obtained by adding an acid such as formic acid,trifluoroacetic acid, paratoluenesulfonic acid, etc. to the compound tiin a solvent such as acetone, acetonitrile, ethanol, water, etc. or in amixed solvent thereof, or adding sulfuric acid in a formic acid solvent,and performing a reaction at 0° C. to 90° C., preferably 20° C. to 80°C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.

Fifth Step

A compound tm can be obtained by adding a compound t1 and acetic acid tothe compound tj or the compound tk in the presence of a solvent such aschloroform, dichloromethane, THF, etc., and performing a reaction at 0°C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours,preferably 1 hour to 12 hours.

Sixth Step

A compound to can be obtained by adding a compound tn and acetic acid tothe compound tj or the compound tk in the presence of a solvent such aschloroform, dichloromethane, THF, etc., and performing a reaction at 0°C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours,preferably 1 hour to 12 hours.

Seventh Step

A compound tp can be obtained by adding a compound B-L¹ corresponding toan objective compound to the compound to in the presence of a solventsuch as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, andperforming a reaction at 0° C. to 80° C., preferably 20° C. to 60° C.for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.

Synthesis of Compound vf (See: Examples 583 and 584)

(wherein Y1 is a substituent corresponding to R³ or R^(3a), and Y2 is asubstituent corresponding to R¹¹ or R^(11a). Other each symbol is asdefined above.)

First Step

A compound vc can be obtained by adding a compound vb having asubstituent corresponding to an objective compound to a compound va inthe presence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at −20° C.to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours,preferably 1 hour to 12 hours.

Alternatively, a compound vc can be obtained by adding an acylatingreagent such as diphenylchlorophosphate, thionyl chloride, oxalylchloride etc. to a compound va in the presence or absence of a base suchas pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole,etc. in the presence of a solvent such as THF, dioxane, dichloromethane,DMF etc., thereby, generating acid chloride, and adding a compound vbhaving a substituent corresponding to an objective compound, andperforming a reaction at −20° C. to 60° C., preferably −10° C. to 40° C.for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.

Second Step

A compound vd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound vc inthe presence of a solvent such as DMF, DMA, NMP, THF, etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.

Third Step

A deprotecting reaction of an acetal protective group of the compound vdcan be performed by the general method described in Protective Groups inOrganic Synthesis, Theodora W Green (John Wiley & Sons) etc. Thereafter,a generated aldehyde group is subjected to an intramolecular reaction,thereby, a compound ve can be obtained.

For example, a compound ve can be obtained by adding acetic acid and/orparatoluenesulfonic acid to the compound vd in the presence of a solventsuch as DMF, toluene, THF, etc., and performing a reaction at 10° C. to80° C., preferably 30° C. to 60° C. for 0.5 hour to 12 hours, preferably1 hour to 6 hours.

Fourth Step

A compound vf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate, etc. to the compound ve in thepresence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 400° C. for 0.1 hour to 48 hours, preferably 1 hourto 24 hours.

The present invention will be explained in more detail below by way ofExamples and Reference Examples, as well as Test Examples of the presentinvention, but the present invention is not limited by them.

Example 1

First Step

A dichloromethane (90 mL) solution of compound 1A (12.8 g, 89.4 mmol)and pyridine (8.50 g, 107 mmol) was cooled to 1 to 3° C., and adichloromethane (90 mL) solution of benzyloxyacetyl chloride (19.8 g,107 mmol) was added dropwise over 50 minutes while the same temperaturewas retained. After the reaction solution was stirred at the sametemperature for 30 minutes, temperature was gradually raised to 15° C.over 60 minutes, and ice water was added. The dichloromethane layer wasseparated, and the aqueous layer was extracted with dichloromethaneonce. The combined extracts were washed with water three times, washedwith an aqueous saturated sodium chloride solution, and dried. Thesolvent was distilled off, and the resulting oil was purified by silicagel column chromatography. The materials were eluted firstly withn-hexane and, then, with n-hexane-ethyl acetate (1:1, v/v).Concentration of objective fraction afforded 22.2 g of compound 1B as anoil.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.90 (3H, brs), 3.24 (3H,brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.58 (2H, s), 7.25-7.38 (5H,m), 7.72 (1H, s).

Second Step

A 1N lithiumhexamethyldisilazane THF solution (4.29 ml, 4.29 mmol) wascooled to −78° C., and a THF solution (4 ml) of compound 1B (500 mg,1.72 mmol) and cinnamoyl chloride (343.2 mg, 2.06 mmol) were addeddropwise thereto over 3 minutes while the same temperature was retained.After the reaction solution was stirred at the same temperature for 25minutes, 2N hydrochloric acid (10 ml) was added, and the mixture wasfurther stirred at room temperature for 10 minutes. To the reactionsolution was added ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate three times. Thecombined extracts were dried with sodium sulfate. The solvent wasdistilled off, and the resulting oil was purified by silica gel columnchromatography. From fraction eluted with n-hexane-ethyl acetate (1:1,v/v), 364.3 mg (yield 56%) of compound 1C was obtained as a solid.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 5.27(2H, s), 6.99 (1H, d, J=16.2 Hz), 7.23 (1H, d, J=16.2), 7.26-7.48 (10H,m), 8.45 (1H, s).

Third Step

To a MeCN (5 ml) solution of compound 1C and ruthenium chloride (2.76mg, 0.0133 mmol) was added dropwise an aqueous solution (8 ml) of sodiumperiodate (625.8 mg, 2.93 mmol) and 96% sulfuric acid (287.4 mg, 2.93mmol) over 10 minutes at room temperature under nitrogen stream. Afterthe reaction solution was stirred at the same temperature for 5 minutes,ethyl acetate was added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate two times. The combinedextracts were dried with sodium sulfate. The solvent was distilled off,and the resulting oil was purified by silica gel column chromatography.From fraction eluted with n-hexane-ethyl acetate (1:1, v/v), 303.2 mg(yield 75%) of compound 1D was obtained as an oil.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=6.9 Hz), 4.40 (2H, q, J=6.9 Hz), 5.54(2H, s), 7.37 (5H, s), 8.48 (1H, s), 9.85 (1H, s).

Fourth Step

To a MeCN (15 ml) solution of compound 1D (1.00 g, 3.31 mmol) was addedan aqueous solution (10 ml) of 96% sulfuric acid (421.7 mg, 4.30 mmol)and amidosululic acid (642.7 mg, 6.62 mmol) at room temperature, themixture was stirred, and an aqueous solution (10 ml) of sodium chlorite(388.9 mg, 4.30 mmol) was added dropwise over 5 minutes while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 5 minutes, an aqueous saturated sodium chloridesolution was added, and the mixture was extracted with ethyl acetatethree times. The combined extracts were dried with sodium sulfate. Thesolvent was distilled off, and the resulting oil was purified by silicagel column chromatography. The materials were eluted firstly withchloroform and, then, with chloroform-MeOH (7:3, v/v). Concentration ofobjective fraction afforded 748.8 mg (yield 71%) of compound 1E as anoil.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 3.93 (1H, br s), 4.40 (2H, q,J=7.2 Hz), 5.61 (2H, s), 7.38-7.44 (10H, m), 8.52 (1H, s).

Fifth Step

To a DMF (10 ml) solution of compound 1E (1.00 g, 3.14 mmol) were addedWSC HCl (1.20 g, 6.28 mmol) and HOBt (551.6 mg, 4.08 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 90minutes. The reaction solution was cooled to 0° C., and a DMF (2 ml)solution of 2-methoxyethanamine (236.0 mg, 3.14 mmol) was added dropwiseover 3 minutes. The reaction solution was stirred at the sametemperature for 1 hour, water was added, and the mixture was extractedwith ethyl acetate three times. The extract was washed with water threetimes, and dried with sodium sulfate. The solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v)and, then, with n-hexane-ethyl acetate (1:9, v/v). Concentration ofobjective fraction afforded 928.5 mg (yield 79%) of compound 1F as anoil.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 3.29 (3H, s), 3.41 (2H, t,J=5.4 Hz), 3.47-3.53 (2H, m), 4.39 (2H, q, J=7.2 Hz), 5.44 (2H, s), 7.36(3H, m), 7.44-7.47 (2H, m), 8.07 (1H, br s), 8.54 (1H, s).

Sixth Step

A xylene (2 ml) solution of compound 1F (500 mg, 1.33 mmol) and(S)-2-amino-3-phenylpropan-1-ol (604.2 mg, 4.0 mmol) was heated to 120°C., and stirred for 30 minutes. After the reaction solution was cooledto room temperature, and the solvent was distilled off, the resultingoil was purified by silica gel chromatography. The materials were elutedfirstly with chloroform and, then, with chloroform-MeOH (9:1, v/v).Concentration of objective fraction afforded 487 mg (yield 72%) ofcompound 1G as an oil.

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=6.9 Hz), 2.24-2.34 (1H, m), 2.24-3.00(1H, m), 3.03-3.16 (1H, m), 3.05 (3H, m), 3.25-3.32 (2H, m), 4.13-4.19(1H, m), 4.17-4.30 (1H, m), 4.36-4.47 (1H, m), 4.51-4.54 (1H, m), 4.55(1H, d, J=10.5 Hz), 5.78 (1H, t, J=6.9 Hz), 7.17-7.26 (4H, m), 7.28-7.35(5H, m), 7.49 (1H, t, J=5.4 Hz), 6.32 (1H, s).

Seventh Step

To a THF (6 ml) solution of compound 1G (2.86 g, 5.63 mmol) andtriphenylphosphine (2.21 g, 8.45 mmol) was added dropwise a DEAD 40 wt %toluene solution (3.68 g, 8.45 mmol) at room temperature over 3 minutes.The reaction solution was stirred at the same temperature for 30minutes, the solvent was distilled off, and the resulting oil waspurified by silica gel chromatography. From a fraction eluted with ethylacetate-MeOH (9:1, v/v), 1.37 g (yield 50%) of compound 1H was obtainedas an oil.

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 3.07 (2H, d, J=6.9 Hz), 3.33(3H, s), 3.57-3.80 (4H, m), 3.95 (1H, dd, J=3.0 Hz, 6.6 Hz), 4.01-4.14(1H, m), 4.16-4.34 (2H, m), 5.24 (1H, d, J=9.9 Hz), 5.51 (1H, d, J=9.9Hz), 7.01-7.03 (2H, m), 7.21-7.37 (5H, m), 7.41-7.58 (1H, m), 7.64-7.69(2H, m).

Eighth Step

To an EtOH (6 ml) solution of compound 1H (1.0 g, 2.04 mmol) was added a2N aqueous sodium hydroxide solution (6 ml), and the mixture was stirredat room temperature for 30 minutes. The reaction solution wasneutralized with 2N hydrochloric acid, and the precipitated solid wasfiltered, and dried to obtain 754 mg (yield 80%) of compound 1I.

¹H-NMR (CDCl₃) δ: 3.10 (2H, d, J=7.8 Hz), 3.33 (3H, s), 3.57-3.69 (4H,m), 3.82-3.90 (1H, m), 3.95 (1H, dd, J=3.3 Hz, 13.8 Hz), 4.36 (1H, dd,J=6.3 Hz, 7.5 Hz), 5.36 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz),6.98-7.01 (2H, m), 7.28-7.39 (6H, m), 7.59 (2H, dd, J=1.8 Hz, 8.1 Hz),7.87 (1H, s).

Ninth Step

Compound 1I (1.0 g, 2.16 mmol) was dissolved in THF (10 ml), 10%Pd—C(200 mg) was added, and the mixture was subjected to a catalyticreduction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. The resulting residue was washed withether to obtain 512 mg (yield 64%) of compound 1.

¹H-NMR (CDCl₃) δ: 6.24 (2H, d, J=6.3 Hz), 3.36 (3H, s), 3.60-3.86 (5H,m), 4.14 (1H, d, J=12.9 Hz), 4.47 (1H, s), 7.03-7.05 (2H, m), 7.30-7.35(3H, m), 7.88 (1H, s), 12.68 (1H, s), 14.83 (1H, s).

Example 2

First Step

To (S)-tert-butyl 3-hydroxy-1,1-diphenylpropan-2-ylcarbamate (5.00 g,15.3 mmol) was added trifluoroacetic acid (40 ml), and the mixture wasstirred for 1 hour under ice-cooling. After trifluoroacetic acid wasdistilled off, toluene was added, and distilled off again under reducedpressure to obtain crude (S)-2-amino-3,3-diphenylpropan-1-ol. To theresulting (S)-2-amino-3,3-diphenylpropan-1-ol were added compound 1F(5.73 g, 15.3 mmol), toluene (50 ml), and triethylamine (6.4 ml, 45.8mmol), the mixture was stirred at 90° C. for 1 hour, and cooled to roomtemperature and, thereafter, the solvent was distilled off. To theresulting residue was added dichloromethane, and the mixture was washedwith 2N hydrochloric acid, an aqueous saturated sodium bicarbonatesolution, and an aqueous saturated sodium chloride solution. Afterseparation of the organic layer, after magnesium sulfate was added, themixture was filtered with celite, and the filtrate was distilled off toobtain candy-like compound 2A (9.12 g)

MS: m/z=585.2 [M+H]⁺.

Second Step

The compound 2A (8.60 g, 14.7 mmol) and triphenylphosphine (7.72 g, 29.4mmol) were dissolved in tetrahydrofuran (90 ml), and a 2.2M toluenesolution of diethyl azodicarboxylate (10.0 ml, 22.0 mmol) was addeddropwise under ice-cooling. After the mixture was stirred for 2 hoursunder ice-cooling, and for 18 hours under room temperature, the solventwas distilled off. The resulting residue was purified by silica gelcolumn chromatography to obtain foamy compound 2B (3.88 g, 6.85 mmol).

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, m), 3.11 (3H, s), 3.16 (1H, m), 3.28 (1H,m), 3.76 (1H, m), 3.97-4.13 (3H, m), 4.31 (1H, d, J=11.3 Hz), 5.08 (2H,s), 5.52 (1H, d, J=12.0 Hz), 7.18-7.25 (6H, m), 7.25-7.45 (6H, m),7.55-7.66 (6H, m).

MS: m/z=567.7 [M+H]⁺.

Third Step

To compound 2B (3.4 g, 6.0 mmol) were added ethanol (36 ml), water (12ml), and a 2N aqueous sodium hydroxide solution (4.5 ml, 9.0 mmol), andthe mixture was stirred at room temperature for 40 minutes, thereafter,ethanol (10 ml) and water (10 ml) were added, and the mixture wasfurther stirred for 30 minutes. Ethanol was distilled off, ethyl acetateand water were added, and the mixture was stirred vigorously and,thereafter, layers were separated. The ethyl acetate layer was washedwith 2N sodium hydroxide three times, and the aqueous layers werecombined into one aqueous layer. To the aqueous layer was added ethylacetate, the mixture was neutralized using 2N hydrochloric acid, thenthe mixture was stirred vigorously and, thereafter, the ethyl acetatelayer was separated. To the ethyl acetate layer was added magnesiumsulfate, the mixture was filtered with celite, and the filtrate wasdistilled off. The resulting residue was dissolved in MeOH, and thesolvent was distilled off to obtain a solid of compound 2C (3.0 g, 5.64mmol).

¹H-NMR (DMSO-d₆) δ: 3.11 (3H, s), 3.16 (1H, m), 3.25 (1H, m), 3.75 (1H,m), 4.11 (1H, m), 4.36 (1H, d, J=11.6 Hz), 5.18 (2H, dd, J=15.7 Hz, 10.4Hz), 5.71 (1H, d, J=11.6 Hz), 7.08-7.20 (5H, m), 7.29-7.45 (6H, m), 7.55(2H, d, J=6.7 Hz), 7.61 (2H, d, J=7.5 Hz), 7.98 (1H, s).

MS: m/z=539.4 [M+H]⁺.

Fourth Step

To compound 2C (1.50 g, 2.79 mmol) were added methanol (22 ml), and 10%palladium carbon-50% wet (150 mg), and the mixture was stirred for 1hour under hydrogen atmosphere. Ethyl acetate (44 ml) was added, themixture was filtered with celite, and the filtrate was distilled off.The resulting residue was dissolved in methanol (20 ml), water (10 ml)was added, and methanol was distilled off. The precipitate was filtered,and dried to obtain compound 2 (1.15 g, 2.56 mmol).

¹H-NMR (DMSO-d₆) δ: 3.15 (3H, s), 3.50-3.70 (5H, m), 4.19 (1H, dd,J=13.8 Hz, 3.1 Hz), 4.49 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=9.6 Hz),7.10-7.27 (6H, m), 7.34 (1H, m), 7.46 (2H, t, J=7.5 Hz), 7.63 (2H, t,J=7.7 Hz), 7.94 (1H, s), 12.94 (1H, s), 15.08 (1H, s).

MS: m/z=449.4 [M+H]⁺.

Example 3

According to Example 2, compound 3 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.15 (1H, m), 3.26 (3H, s), 3.52-3.70 (4H, m),3.70-3.80 (2H, m), 4.10 (1H, d, J=12.9 Hz), 4.92 (1H, brs), 6.98 (1H, t,J=7.4 Hz), 7.03 (1H, brs), 7.08 (1H, t, 7.6 Hz), 7.34 (1H, d, J=7.8 Hz),7.47 (1H, d, J=7.3 Hz), 7.80 (1H, s), 10.94 (1H, brs), 15.38 (1H, brs).

MS: m/z=412.4 [M+H]⁺.

Example 4

According to Example 2, compound 4 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.46-3.72 (5H, m), 4.16 (1H, d, J=12.6Hz), 4.48 (1H, d, J=10.9 Hz), 5.77 (1H, d, J=11.6 Hz), 7.10-7.27 (6H,m), 7.32 (1H, m), 7.44 (2H, m), 7.61 (2H, m), 7.93 (1H, s), 15.04 (1H,s).

MS: m/z=449.3 [M+H]⁺.

Example 5

According to Example 2, compound 5 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.28 (3H, s), 3.52-3.68 (4H, m), 4.06 (1H, m), 4.25(2H, m), 4.41 (1H, brs), 4.56 (1H, d, J=13.6 Hz), 4.82 (1H, d, J=13.9Hz), 6.74 (2H, d, J=7.6 Hz), 6.92 (1H, t, J=7.20 Hz), 7.25 (2H, t, J=7.8Hz), 8.58 (1H, s), 12.48 (1H, brs), 15.55 (1H, brs).

MS: m/z=389.4 [M+H]⁺.

Example 6

According to Example 2, compound 6 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.16 (1H, m), 3.26 (3H, s), 3.50-3.70 (4H, m),3.70-3.80 (2H, m), 4.10 (1H, d, J=13.4 Hz), 4.92 (1H, brs), 6.98 (1H, t,J=7.1 Hz), 7.03 (1H, brs), 7.08 (1H, t, J=7.3 Hz), 7.34 (1H, d, J=7.8Hz), 7.48 (1H, d, J=7.3 Hz), 7.81 (1H, s), 12.91 (1H, s), 15.36 (1H, s).

MS: m/z=412.4 [M+H]⁺.

Example 7

According to Example 2, compound 7 was synthesized by the same method.

¹H-NMR (DMSO-d₆) δ: 0.85-0.95 (2H, m), 1.05-1.25 (5H, m), 1.45-1.80 (8H,m), 3.28 (3H, s), 3.46 (1H, m), 3.58 (1H, m), 3.72 (1H, d, J=13.9 Hz),3.93 (1H, m), 4.04 (1H, d, J=13.1 Hz), 4.88 (1H, s), 8.56 (1H, s), 12.80(1H, s), 15.51 (1H, s).

MS: m/z=379.3 [M+H]⁺.

Example 8

According to Example 2, compound 8 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.07 (2H, m), 2.55 (1H, m), 2.74 (1H, m), 3.17 (1H,s), 3.23 (3H, s), 3.48-3.65 (4H, m), 3.79 (1H, d, J=13.6 Hz), 3.87 (1H,m), 4.09 (1H, d, J=13.6 Hz), 4.80 (1H, s), 7.10-7.29 (5H, m), 8.59 (1H,s), 12.77 (1H, s), 15.49 (1H, s).

MS: m/z=387.3 [M+H]⁺.

Example 9

According to Example 2, compound 9 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, dd, J=14.5 Hz, J2=8.5 Hz), 2.93 (1H, dd,J=14.4 Hz, 5.6 Hz), 3.21 (3H, s), 3.40-3.55 (4H, m), 3.77 (2H, s), 3.82(1H, d, J=13.1 Hz), 3.88 (1H, m), 4.13 (1H, d, J=13.6 Hz), 4.85 (1H, s),7.20-7.35 (5H, m), 8.61 (1H, s), 12.79 (1H, s), 15.43 (1H, s).

MS: m/z=419.3 [M+H]⁺.

Example 10

According to Example 2, compound 10 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.2 Hz), 3.29 (3H, s), 3.43 (1H, m),3.58 (2H, m), 3.94 (1H, m), 4.12 (1H, brs), 4.41 (1H, d, J=13.6 Hz),4.49 (1H, d, J=13.1 Hz), 8.59 (1H, s), 12.65 (1H, s), 15.53 (1H, s).

MS: m/z=297.2 [M+H]⁺.

Example 11

According to Example 2, compound 11 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.46 (4H, brs), 1.76-1.90 (2H, m), 2.22 (1H, brs),3.27 (3H, s), 3.57 (1H, d, J=5.3 Hz), 4.07 (1H, m), 4.69 (1H, m), 8.47(1H, s), 13.04 (1H, s), 15.52 (1H, s).

MS: m/z=337.2 [M+H]⁺.

Example 12

First Step

Compound 12A (1.53 g, 5.80 mmol) were dissolved in THF (6 ml) and water(6 ml), potassium carbonate (2.41 g, 17.4 mmol) was added, the mixturewas stirred, and benzyl chloroformate (1.09 g, 6.38 mmol) was addeddropwise at 0° C. After stirring at 0° C. for 10 minutes, the mixturewas stirred at room temperature for 2 hours. The reaction solution waspoured into sodium bicarbonate water, and the mixture was extracted withethyl acetate. The extract was washed with 1N hydrochloric acid and anaqueous saturated sodium chloride solution, and dried with sodiumsulfate. The solvent was distilled off to obtain 2.32 g of compound 12Bas a colorless gummy solid.

¹H-NMR (CDCl₃) δ: 1.98 (1H, brs), 3.55 (1H, m), 3.75 (1H, m), 4.20 (1H,d, J=10.5 Hz), 4.58 (1H, m), 4.83 (1H, brs), 5.07 (2H, s), 7.16-7.39(15H, m).

Second Step

The compound 12B (1.94 g, 5.37 mmol), triphenylphosphine (2.11 g, 8.05mmol) and phthalimide (948 mg, 6.44 mmol) were added to THF (20 ml), anddiisopropyl azodicarboxylate (2.2M in toluene, 3.66 ml, 8.05 mmol) wasadded dropwise at room temperature. After stirring at room temperaturefor 4 hours, the solvent was distilled off under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 12C as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.73 (2H, m), 4.05 (1H, d, J=10.1 Hz), 4.70 (1H, d,J=9.6 Hz), 4.77 (2H, d, J=7.2 Hz) 5.02 (1H, m), 7.03-7.42 (15H, m), 7.68(2H, dd, J=5.7, 2.1 Hz), 7.78 (2H, dd, J=5.7, 2.1 Hz).

Third Step

The compound 12C (2.39 g, 4.87 mmol) was added to THF (20 ml) andmethanol (20 ml), hydrazine hydrate (4.88 g, 97.4 mmol) was added, andthe mixture was stirred at 50° C. for 4 hours. The white precipitate wasremoved by filtration, and washed with methanol. After the filtrate wasdistilled off under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1, v/v)to obtain 1.41 g of compound 12D as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.63 (1H, dd, J=13.2, 5.8 Hz), 2.86 (1H, d, J=9.9 Hz),4.07 (1H, d, J=10.4 Hz), 4.53 (1H, m), 4.81 (1H, m), 5.00 (2H, d, 8.4Hz), 7.20-7.36 (10H, m).

Fourth Step

Compound 12D (1.41 g, 3.91 mmol) was dissolved in THF (15 ml), and Boc₂O(896 mg, 4.11 mmol) was added at room temperature. After stirring for1.5 hours, the solvent was concentrated under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.77 g of compound 12E as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 3.23 (2H, brm), 3.97 (1H, d, J=9.8 Hz),4.58-4.80 (3H, m), 5.00 (2H, d, J=9.8 Hz), 7.15-7.29 (10H, m).

Fifth Step

Compound 12E (1.73 g, 3.76 mmol) and palladium-active carbon (10%, wet,200 mg) were added to methanol (20 ml), and the mixture was stirred atroom temperature for 1 hour under hydrogen atmosphere. After filtrationwith celite, the solvent was concentrated under reduced pressure toobtain 1.01 g of a colorless oily substance 12F.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.82 (1H, m), 3.31 (1H, m), 3.73 (2H, d,J=6.9 Hz), 4.98 (1H, s), 7.18-7.39 (10H, m).

Sixth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (974 mg, 3.06mmol) obtained by the method shown in Reference Example 1, and 12F (999mg, 3.06 mmol) were added to toluene (10 ml), and the mixture wasstirred at 110° C. for 5 hours. After the solvent was distilled offunder reduced pressure, the resulting crude product was purified bysilica gel column chromatography (chloroform-methanol, 98:2, v/v) toobtain 1.51 g of compound 12G as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 3.40 (1H, m), 3.53 (1H, m), 3.82 (3H,s), 3.91 (3H, s), 4.29 (1H, d, J=11.3 Hz), 4.78 (1H, m), 4.82 (1H, m),5.11 (1.9H, d, J=7.5 Hz), 7.10-7.38 (10H, m), 8.27 (1H, s).

Seventh Step

To compound 12G (1.45 g, 2.31 mmol) was added 4N HCl (ethyl acetatesolution, 20 ml), and the mixture was stirred at room temperature for1.5 hours. After the solvent was distilled off under reduced pressure,sodium bicarbonate water was added, and the mixture was stirred at roomtemperature for 1.5 hours. This was extracted with chloroform, and driedwith sodium sulfate. After the solvent was distilled off under reducedpressure, the resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 95:5, v/v) to obtain 1.01 g ofcompound 12H as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.40 (1H, dd, J=13.6, 6.6 Hz), 3.78 (3H, s), 3.80 (1H,m), 4.37 (1H, d, J=11.6 Hz), 4.59 (1H, d, J=11.0 Hz), 5.43 (2H, d,J=10.2 Hz), 5.93 (1H, d, J=5.8 Hz), 7.03-7.21 (5H, m), 7.37 (9H, m),7.63 (2H, m).

Eighth Step

Compound 12H (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (165 mg, 0.50 mmol) was added. After stirring at roomtemperature for 30 minutes, iodomethane (0.032 ml, 0.50 mmol) was added,and the mixture was stirred at room temperature for 3.5 hours. Thereaction solution was poured into water, and the mixture was extractedwith ethyl acetate, and dried with sodium sulfate. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 95:5,v/v) to obtain 49 mg of compound 121 as a colorless solid.

Ninth Step

Compound 12I (49 mg, 0.096 mmol) was dissolved in THF (0.5 ml) andmethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.24 ml, 0.48mmol) was added at room temperature, and the mixture was stirred for 1.5hours. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 54 mg ofcompound 12J was obtained as a colorless solid.

MS: m/z=481 [M+H]⁺.

Tenth Step

To compound 12J obtained in the ninth step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 26 mg of compound 12 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.01 (3H, s), 3.26 (1H, t, J=14.4 Hz), 4.23 (1H, dd,J=13.5, 3.8 Hz), 4.57 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=11.3 Hz),7.16-7.70 (10H, m), 8.00 (1H, s), 13.00 (1H, s), 15.10 (1H, s).

MS: m/z=405 [M+H]⁺.

Example 13

According to Example 12, compound 13 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.05 (3H, t, J=6.9 Hz), 3.43-3.65 (3H, m), 4.22 (1H,d, J=10.6 Hz), 4.55 (1H, d, J=11.6 Hz), 5.81 (1H, d, J=10.1 Hz),7.15-7.68 (10H, m), 7.97 (1H, s), 12.96 (1H, s), 15.07 (1H, s).

MS: m/z=463 [M+H]⁺.

Example 14

According to Example 12, compound 14 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 0.98 (3H, t, J=7.17 Hz), 3.44-3.64 (3H, m), 4.15(1H, dd, J=13.7, 3.5 Hz), 4.45 (1H, d, J=11.6 Hz), 5.79 (1H, d, J=12.2Hz), 7.08-7.63 (10H, m), 7.89 (1H, s), 13.01 (1H, s), 15.06 (1H, s).

MS: m/z=419 [M+H]⁺.

Example 15

According to Example 12, compound 15 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.22 (1H, s), 3.47 (1H, d, J=13.3 Hz), 4.17 (2H, m),4.44 (2H, dd, J=16.7, 3.0 Hz), 5.79 (1H, d, J=12.2 Hz), 7.10-7.64 (10H,m), 7.98 (1H, s), 12.56 (1H, s), 15.05 (1H, brs).

Example 16

According to Example 12, compound 16 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.24 (1H, d, J=13.2 Hz), 4.23 (1H, m), 4.25 (1H, d,J=14.7 Hz), 4.40 (1H, d, J=14.8 Hz), 4.92 (1H, d, J=15.4 Hz), 5.79 (1H,m), 7.03-7.48 (10H, m), 7.93 (1H, s), 12.82 (1H, s), 15.06 (1H, s).

Example 17

According to Example 12, compound 17 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.23 (1H, d, J=13.4 Hz), 4.22 (1H, m), 4.25 (1H, d,J=12.0 Hz), 4.45 (1H, d, J=14.9 Hz), 4.93 (1H, d, J=15.3 Hz), 5.77 (1H,d, J=11.6 Hz), 7.09-7.56 (10H, m), 7.92 (1H, s), 12.74 (1H, s), 15.06(1H, s).

Example 18

According to Example 12, compound 18 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.63 (2H, m), 3.20 (3H, s), 3.44 (5H, m), 4.19 (1H,d, J=10.2 Hz), 4.51 (1H, d, J=11.8 Hz), 5.80 (1H, d, J=11.0 Hz),7.13-7.65 (10H, m), 7.93 (1H, s), 13.02 (1H, s).

MS: m/z=463 [M+H]⁺.

Example 19

According to Example 12, compound 19 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.15 (1H, d, J=9.5 Hz), 3.95 (1H, dd, J=13.5, 3.4Hz), 4.51 (1H, d, J=11.6 Hz), 5.74 (1H, d, J=11.1 Hz), 7.11-7.62 (10H,m), 7.93 (1H, s), 9.34 (1H, s), 12.97 (1H, s), 15.07 (1H, brs).

MS: m/z=391 [M+H]⁺.

Example 20

According to Example 12, compound 20 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.26 (1H, m), 4.24 (1H, m), 4.27 (1H, d, J=12.0 Hz),4.41 (1H, d, J=14.8 Hz), 4.87 (1H, d, J=14.9 Hz), 5.75 (1H, d, J=7.6Hz), 7.09-7.77 (12H, m), 7.93 (1H, s), 8.52 (2H, m), 12.79 (1H, s),15.07 (1H, brs).

MS: m/z=482 [M+H]⁺.

Example 21

According to Example 12, compound 21 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 0.62 (3H, d, J=6.9 Hz), 0.82 (3H, d, J=6.6 Hz), 3.18(1H, m), 3.75 (1H, d, J=10.2 Hz), 4.25 (1H, d, J=11.8 Hz), 4.58 (1H, m),5.65 (1H, d, J=11.3 Hz), 6.89-7.43 (10H, m), 7.67 (1H, s), 12.94 (1H,s).

MS: m/z=433 [M+H]⁺.

Example 22

According to Example 12, compound 22 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.07-1.70 (5H, m), 3.04-3.34 (5H, m), 3.82 (2H, dm),4.18 (1H, d, J=10.2 Hz), 4.42 (1H, d, J=12.0 Hz), 5.81 (1H, d, J=11.7Hz), 7.11-7.59 (10H, m), 7.86 (1H, s), 12.96 (1H, s), 15.07 (1H, brs).

MS: m/z=489 [M+H]⁺.

Example 23

According to Example 12, compound 23 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 0.01-0.79 (5H, m), 3.05 (1H, dd, J=14.1, 7.5 Hz),3.49-3.59 (2H, m), 4.16 (1H, dd, J=14.0, 3.3 Hz), 4.50 (1H, d, J=11.9Hz), 5.82 (1H, d, J=11.1 Hz), 7.11-7.62 (10H, m), 7.89 (1H, s), 12.99(1H, s), 15.07 (1H, brs).

MS: m/z=445 [M+H]⁺.

Example 24

According to Example 12, compound 24 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.23 (1H, d, J=13.7 Hz), 4.16 (1H, dd, J=13.2, 3.3Hz), 4.19 (2H, d, J=12.0 Hz), 4.38 (1H, d, J=14.6 Hz), 4.84 (1H, d,J=14.6 Hz), 5.72 (1H, d, J=11.4 Hz), 7.08-7.33 (15H, m), 7.98 (1H, s),12.88 (1H, s), 15.07 (1H, s).

MS: m/z=481 [M+H]⁺.

Example 25

According to Example 12, compound 25 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.37 (1H, m), 4.21 (1H, dd, J=14.4,3.9 Hz), 4.40 (1H, dd, J=11.7 Hz), 4.45 (1H, d, J=15.3 Hz), 4.81 (1H, d,J=15.4 Hz), 5.78 (1H, d, J=12.0 Hz), 6.30 (1H, s), 7.09-7.42 (10H, m),7.95 (1H, s), 12.65 (1H, s), 15.07 (1H, s).

MS: m/z=486 [M+H]⁺.

Example 26

According to Example 12, compound 26 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.20-1.77 (6H, m), 3.11-3.61 (6H, m), 4.21 (1H, d,J=9.9 Hz), 4.53 (1H, d, J=11.7 Hz), 5.80 (1H, d, J=11.8 Hz), 7.14-7.65(10H, m), 7.95 (1H, s), 12.95 (1H, brs), 15.06 (1H, brs).

MS: m/z=489 [M+H]⁺.

Example 27

According to Example 12, compound 27 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.36 (1H, m), 4.28 (1H, d, J=12.0 Hz), 4.54 (1H, d,J=11.4 Hz), 4.62 (1H, d, J=15.3 Hz), 4.79 (1H, d, J=15.4 Hz), 5.77 (1H,d, J=9.9 Hz), 7.09-7.79 (13H, m), 7.98 (1H, s), 8.46 (1H, d, J=4.6 Hz),12.82 (1H, brs), 15.06 (1H, brs).

MS: m/z=482 [M+H]⁺.

Example 28

First Step

Compound 28A (3.20 g, 17.1 mmol) was added to THF (20 ml), triethylamine(2.60 ml, 18.8 mmol) was added, and the mixture was stirred at roomtemperature for 10 minutes. After Boc₂O (4.09 g, 18.8 mmol) was added atroom temperature, the mixture was stirred for 2 hours. The solvent wasdistilled off under reduced pressure, water was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous saturated sodium chloride solution, and dried with sodiumsulfate. The solvent was distilled off under reduced pressure to obtain5.17 g of compound 28B as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 2.77 (2H, m), 3.03-3.12 (1H, m), 3.38(1H, m), 3.90-3.98 (1H, m), 4.93 (1H, brs), 7.20-7.35 (5H, m).

Second Step

Compound 28B (4.29 g, 17.1 mmol), triphenylphosphine (5.37 g, 20.5 mmol)and phthalimide (2.76 g, 18.8 mmol) were added to THF (60 ml), anddiethyl azodicarboxylate (2.2M in toluene, 11.6 ml, 25.6 mmol) was addeddropwise at room temperature. After the mixture was stirred at roomtemperature for 1 hour, the solvent was distilled off under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain 6.13 g ofcompound 28C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 3.14 (1H, dd, J=13.8, 6.2 Hz), 3.39 (2H,m), 3.87 (1H, m), 4.67 (1H, m), 4.81 (1H, brs), 7.16-7.19 (5H, m), 7.66(2H, dd, J=5.3, 3.1 Hz), 7.75 (2H, dd, J=5.7, 3.0 Hz).

Third Step

Compound 28C (1.00 g, 2.63 mmol) was added to THF (7 ml) and methanol (7ml), hydrazine hydrate (2.63 g, 52.6 mmol) was added, and the mixturewas stirred at 50° C. for 2 hours. The white precipitate was removed byfiltration, and washed with methanol. After the filtrate was distilledoff under reduced pressure, the resulting crude product was purified byamino column chromatography (chloroform-methanol, 99:1, v/v) to obtain249 mg of compound 28D as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.95 (2H, brs), 2.55-3.31 (5H, m), 5.06(1H, brs), 7.18-7.33 (5H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (313 mg, 0.983mmol) and 28D (246 mg, 0.983 mmol) were added to toluene (3 ml), and themixture was stirred at 100° C. for 2.5 hours. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 98:2,v/v) to obtain 320 mg of compound 28E as a pale yellow gummy substance.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 3.07 (2H, m), 3.56 (2H, m), 3.68 (3H,s), 3.95 (3H, s), 4.26 (1H, s), 4.86 (1H, s), 5.18 (1H, d, J=10.8 Hz),5.22 (1H, d, J=10.8 Hz), 7.01 (2H, m), 7.24-7.38 (8H, m), 8.22 (1H, s).

MS: m/z=551 [M+H]⁺.

Fifth Step

To compound 28E (315 mg, 0.572 mmol) was added 4N HCl (ethyl acetatesolution, 5 ml), and the mixture was stirred at room temperature for 30minutes. After the solvent was distilled off under reduced pressure,aqueous sodium bicarbonate water was added, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 95:5, v/v) to obtain 210 mg of compound 28F as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.07-3.15 (2H, m), 3.34 (1H, dd, J=13.2, 6.0 Hz), 3.74(2H, m), 3.86 (3H, s), 4.12 (1H, m), 5.27 (1H, d, J=10.1 Hz), 5.47 (1H,d, J=10.1 Hz), 6.76 (1H, d, J=6.4 Hz), 7.04 (2H, m), 7.32 (6H, m), 7.62(2H, dd, J=7.7, 1.4 Hz), 7.70 (1H, s).

MS: m/z=419 [M+H]⁺.

Sixth Step

Compound 28F (50 mg, 0.12 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (195 mg, 0.597 mmol) was added. After the mixture was stirredat room temperature for 30 minutes, iodoethane (0.048 ml, 0.60 mmol) wasadded, and the mixture was stirred at room temperature for 3.5 hours.The reaction solution was poured into water, and the mixture wasextracted with ethyl acetate, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 95:5, v/v) to obtain 47 mg of compound 28G as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.2 Hz), 3.00-3.15 (2H, m), 3.28 (1H,dd, J=13.6, 1.6 Hz), 3.48 (1H, m), 3.75 (1H, m), 3.85 (3H, s), 3.88 (1H,dd, J=13.3, 3.2 Hz), 4.15 (1H, m), 5.25 (1H, d, J=9.9 Hz), 5.50 (1H, d,J=9.9 Hz), 7.04 (2H, m), 7.29-7.38 (6H, m), 7.60 (1H, s), 7.68 (2H, m).

MS: m/z=447 [M+H]⁺.

Seventh Step

Compound 28G (47 mg, 0.11 mmol) was dissolved in THF (0.5 ml) andmethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.26 ml, 0.53mmol) was added at room temperature, and the mixture was stirred for 1hour. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 40 mg ofcompound 28H was obtained as a colorless solid.

MS: m/z=433 [M+H]⁺.

Eighth Step

To compound 28H obtained in the seventh step was added trifluoroacteicacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 17 mg of compound 28 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.2 Hz), 3.08 (2H, m), 3.51-3.63 (3H,m), 4.08 (1H, dd, J=13.6, 3.9 Hz), 5.03 (1H, brs), 7.21 (5H, m), 8.07(1H, s), 12.98 (1H, s), 15.07 (1H, brs).

MS: m/z=343 [M+H]⁺.

Example 29

According to Example 28, compound 29 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.96 (2H, d, J=7.6 Hz), 3.46 (1H, d, J=13.3 Hz),4.06 (1H, dd, J=13.6, 3.8 Hz), 4.64 (1H, d, J=14.9 Hz), 4.89 (1H, d,J=14.6 Hz), 4.98 (1H, m), 6.97 (2H, m), 7.10-7.37 (5H, m), 7.57 (1H, m),8.12 (1H, s), 12.75 (1H, s), 15.07 (1H, brs).

Example 30

According to Example 28, compound 30 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.99 (2H, dd, J=7.5, 3.6 Hz), 3.48 (1H, d, J=13.4Hz), 4.09 (1H, dd, J=13.4, 4.0 Hz), 4.73 (1H, d, J=15.1 Hz), 4.92 (1H,d, J=15.1 Hz), 4.99 (1H, m), 6.97 (2H, m), 7.18-7.29 (4H, m), 7.49 (1H,m), 7.61 (1H, m), 8.15 (1H, s), 12.69 (1H, s), 15.06 (1H, brs).

Example 31

According to Example 28, compound 31 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.91 (2H, m), 3.45 (1H, d, J=13.1 Hz), 4.02 (1H, dd,J=13.6, 4.0 Hz), 4.57 (1H, d, J=14.6 Hz), 4.91 (1H, d, J=14.6 Hz), 4.93(1H, m), 6.89 (2H, m), 7.18 (3H, m), 7.40 (5H, m), 8.16 (1H, s), 12.86(1H, brs), 15.06 (1H, brs).

MS: m/z=405 [M+H]⁺.

Example 32

According to Example 28, compound 32 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.10 (2H, m), 3.39 (1H, d, J=13.6 Hz), 3.84 (1H, dd,J=13.6, 4.0 Hz), 4.94 (1H, m), 7.23 (5H, m), 8.19 (1H, s), 9.44 (1H,brs), 12.97 (1H, s), 15.06 (1H, brs).

MS: m/z=315 [M+H]⁺.

Example 33

According to Example 28, compound 33 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.09 (3H, t, J=6.9 Hz), 3.10 (2H, m), 3.42-3.50 (2H,m), 3.71 (5H, m), 4.11 (1H, dd, J=13.6, 3.8 Hz), 4.99 (1H, brs),7.11-7.29 (5H, m), 7.99 (1H, s), 12.88 (1H, s), 15.06 (1H, brs).

MS: m/z=387 [M+H]⁺.

Example 34

According to Example 28, compound 34 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.98(1H, dd, J=13.6, 9.8 Hz), 3.13 (1H, dd, J=13.7, 5.8 Hz), 3.68 (1H, d,J=12.8 Hz), 3.87 (1H, dd, J=13.6, 3.7 Hz), 4.83 (1H, quin, J=6.8 Hz),5.07 (1H, brs), 7.19 (5H, m), 7.90 (1H, s), 13.09 (1H, s), 15.08 (1H,brs).

MS: m/z=357 [M+H]⁺.

Example 35

According to Example 28, compound 35 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.07 (3H, s), 3.14 (2H, m), 3.49 (1H, d, J=13.3 Hz),4.08 (1H, dd, J=13.7, 4.0 Hz), 4.99 (1H, m), 7.13-7.31 (5H, m), 8.18(1H, s), 12.95 (1H, s), 15.06 (1H, brs).

MS: m/z=329 [M+H]⁺.

Example 36

First Step

Compound 12H (460 mg, 0.930 mmol) was dissolved in THF (2.5 ml) andmethanol (2.5 ml), a 2N aqueous sodium hydroxide solution (2.33 ml, 4.65mmol) was added at room temperature, and the mixture was stirred for 1.5hours. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 405 mg ofcompound 36A was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.45 (1H, ddd, J=13.8, 6.9, 1.3 Hz), 3.80 (1H, dd,J=13.5, 2.1 Hz), 4.35 (1H, d, J=11.6 Hz), 4.77 (1H, d, J=11.3 Hz), 5.46(1H, d, J=10.5 Hz), 5.52 (1H, d, J=10.5 Hz), 6.11 (1H, d, J=5.8 Hz),6.94-6.98 (2H, m), 7.17 (3H, m), 7.31-7.46 (8H, m), 7.58 (3H, m).

Second Step

Compound 36A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1, v/v)to obtain 164 mg of compound 36B as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.36 (1H, dd, J=13.0, 7.0 Hz), 3.72 (1H, d, J=11.1Hz), 4.35 (1H, d, J=11.4 Hz), 4.49 (18, d, J=10.2 Hz), 5.38 (1H, d,J=10.5 Hz), 5.43 (1H, d, J=10.4 Hz), 5.94 (1H, d, J=7.2 Hz), 6.29 (1H,d, J=6.6 Hz), 6.38 (1H, d, J=7.5 Hz), 6.99 (2H, m), 7.17 (3H, m), 7.36(8H, m), 7.60 (2H, m).

Third Step

Compound 36B (40 mg, 0.092 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (179 mg, 0.55 mmol) was added. After stirring at roomtemperature for 30 minutes, iodomethane (0.029 ml, 0.46 mmol) was added,and the mixture was stirred at room temperature for 3.5 hours. After thereaction solution was poured into water, and the mixture was extractedwith ethyl acetate, the extract was dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 95:5, v/v) to obtain 44 mg of compound 36C as acolorless gummy substance.

Fourth Step

To compound 36C obtained in the third step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 24 mg of compound 36 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.93 (3H, s), 3.17 (1H, d, J=13.0 Hz), 4.13 (1H, dd,J=13.6, 3.4 Hz), 4.47 (1H, d, J=11.4 Hz), 5.52 (1H, dd, J=9.3, 3.4 Hz),5.99 (1H, d, J=7.3 Hz), 7.18 (4H, m), 7.30 (3H, m), 7.41 (2H, t, J=7.5Hz), 7.60 (2H, d, J=7.2 Hz).

MS: m/z=361 [M+H]⁺.

Example 37

According to Example 36, compound 37 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.16 (2H, d, J=13.3 Hz), 4.05 (1H, d, J=10.5 Hz),4.15 (1H, d, J=11.7 Hz), 4.38 (1H, d, J=14.9 Hz), 4.74 (1H, d, J=14.5Hz), 5.35 (1H, d, J=11.4 Hz), 5.65 (1H, d, J=7.3 Hz), 6.99 (1H, d, J=7.5Hz), 7.21 (15H, m).

MS: m/z=437 [M+H]⁺.

Example 38

According to Example 36, compound 38 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.57 (2H, m), 3.17 (3H, s), 3.21-3.31 (5H, m), 4.07(1H, dd, J=13.5, 3.7 Hz), 4.36 (1H, d, J=11.6 Hz), 5.42 (1H, d, J=9.2Hz), 5.61 (1H, d, J=7.3 Hz), 6.89 (1H, d, J=7.5 Hz), 7.13-7.31 (6H, m),7.40 (2H, t, J=6.3 Hz), 7.57 (2H, d, J=7.3 Hz), 12.31 (1H, brs).

MS: m/z=419 [M+H]⁺.

Example 39

According to Example 36, compound 39 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.12 (1H, dd, J=13.6, 5.5 Hz), 3.87 (1H, d, J=9.5Hz), 4.44 (1H, d, J=11.7 Hz), 5.45 (1H, d, J=10.4 Hz), 5.83 (1H, d,J=7.5 Hz), 7.04 (1H, d, J=7.2 Hz), 7.14-7.31 (6H, m), 7.40 (2H, t, J=7.5Hz), 7.58 (2H, d, J=7.5 Hz), 9.09 (1H, d, J=5.2 Hz).

MS: m/z=347 [M+H]⁺.

Example 40

According to Example 36, compound 40 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.88-3.15 (2H, m), 3.27 (3H, s), 3.53-3.73 (5H, m),3.99 (1H, dd, J=13.27, 3.97 Hz), 4.56-4.60 (1H, m), 5.89 (1H, d, J=7.32Hz), 7.08-7.30 (6H, m).

Example 41

First Step

Compound 41A (290 mg, 0.555 mmol) synthesized according to Example 12was added to diphenyl ether (5 ml), and the mixture was stirred at 245°C. for 1 hour under microwave irradiation. The reaction solution waspoured into n-hexane, and the precipitated solid was filtered. Theresulting crude product was purified by amino column chromatography(chloroform-methanol, 99:1→97:3, v/v) to obtain 86 mg of compound 41B asa colorless solid.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.9 Hz),3.43-3.52 (2H, m), 3.62 (1H, dd, J=13.6, 3.5 Hz), 4.22 (1H, d, J=11.6Hz), 4.52 (1H, d, J=11.6 Hz), 4.86-4.95 (1H, m), 5.37 (1H, d, J=10.2Hz), 5.45 (1H, d, J=10.2 Hz), 5.90 (1H, d, J=7.5 Hz), 6.22 (1H, d, J=7.5Hz), 6.89 (2H, m), 7.15 (3H, m), 7.36 (8H, m), 7.67 (2H, m).

Second Step

To compound 41B obtained in the first step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 45 mg of compound 41 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 0.82 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=6.7 Hz), 3.90(1H, dd, J=13.6, 3.4 Hz), 4.39 (1H, d, J=11.9 Hz), 4.77-4.86 (1H, m),5.50 (1H, d, J=8.6 Hz), 5.69 (1H, d, J=7.4 Hz), 6.92 (1H, d, J=7.4 Hz),7.15-7.48 (8H, m), 7.63 (2H, d, J=7.7 Hz) 12.51 (1H, Brs).

MS: m/z=389 [M+H]⁺.

Example 42

According to Example 41, compound 42 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.51 (5H, m), 4.05 (1H, dd, J=13.9,3.5 Hz), 4.37 (1H, d, J=11.4 Hz), 5.38 (1H, d, J=11.6 Hz), 5.60 (1H, d,J=7.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.22 (6H, m), 7.40 (2H, t, J=7.5 Hz),7.56 (2H, d, J=7.2 Hz).

MS: m/z=405 [M+H]⁺.

Example 43

First Step

Compound 43A (2.00 g, 6.11 mmol), triphenylphosphine (2.40 g, 9.16 mmol)and phthalimide (1.08 g, 7.33 mmol) were added to THF (20 ml), anddiethyl azodicarboxylate (2.2M in toluene, 4.16 ml, 9.16 mmol) was addeddropwise at room temperature. After stirring at room temperature for 3hours, the solvent was distilled off under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 43B as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 1.00 (9H, s), 3.30 (1H, m), 3.61 (1H, dd, J=13.4,10.2 Hz), 4.15 (1H, d, J=12.2 Hz), 4.75 (1H, m), 6.79 (1H, d, J=9.5 Hz),7.25 (15H, m), 7.76-7.89 (4H, m).

Second Step

Compound 43B (2.06 g, 4.51 mmol) was added to THF (20 ml) and methanol(20 ml), hydrazine hydrate (4.52 g, 90.2 mmol) was added, and themixture was stirred at 60° C. for 5 hours. The white precipitate wasremoved by filtration, and washed with methanol. After the filtrate wasdistilled off under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1,v/v), n-hexane was added, and the precipitated solid was filtered toobtain 1.25 g of compound 43C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 2.55 (1H, dd, J=13.3, 6.0 Hz), 2.80 (1H,dd, J=13.3, 3.5 Hz), 3.99 (1H, d, J=10.1 Hz), 4.47 (2H, m), 7.13-7.33(10H, m).

Third Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488 mg, 1.53mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8 ml), and themixture was stirred at 110° C. for 1 hour. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→96:4→94:6, v/v) to obtain 667 mg of compound 43D as a pale yellowgummy substance.

¹H-NMR (CDCl₃) δ: 1.28 (9H, s), 3.63 (3H, s), 3.80 (1H, m), 3.87 (3H,s), 4.02 (1H, dd, J=14.5, 10.1 Hz), 4.21 (1H, d, J=10.4 Hz), 4.47 (2H,m), 5.20 (1H, d, J=10.8 Hz), 5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m),8.05 (1H, s).

MS: m/z=627 [M+H]⁺.

Fourth Step

To compound 43D (664 mg, 1.06 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml), and the mixture was stirred at room temperature for 1hour. After the solvent was distilled off under reduced pressure, THFand saturated sodium bicarbonate water were added, and the mixture wasstirred for 2.5 hours. This was extracted with chloroform, and theextract was dried with sodium sulfate. After the solvent was distilledoff under reduced pressure, methylene chloride-ethyl ether were added,and the precipitated solid was filtered to obtain 458 mg of compound 43Eas a colorless solid.

¹H-NMR (CDCl₃) δ: 3.86 (3H, m), 3.92 (3H, s), 4.41-4.48 (1H, m), 5.32(1H, d, J=10.8 Hz), 5.42 (1H, d, J=10.1 Hz), 5.92 (1H, s), 7.21-7.39(13H, m), 7.59 (2H, m), 7.89 (1H, s).

MS: m/z=495 [M+H]⁺.

Fifth Step

Compound 43E (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (165 mg, 0.51 mmol) was added. After the mixture was stirredat room temperature for 30 minutes, iodomethane (0.025 ml, 0.40 mmol)was added, and the mixture was stirred at room temperature for 1 hour.After the reaction solution was poured into water, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 97:3→95:5, v/v) to obtain 60 mg of compound 43F asa colorless solid.

¹H-NMR (CDCl₃) δ: 2.57 (3H, s), 3.75 (2H, d, J=11.3 Hz), 3.93 (3H, s),4.20-4.29 (2H, m), 5.25 (1H, d, J=9.9 Hz), 5.57 (1H, d, J=9.9 Hz),7.15-7.41 (13H, m), 7.63 (1H, s), 7.72-7.76 (2H, m).

Sixth Step

Compound 43F obtained in the fifth step was dissolved in THF (0.5 ml)and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml,0.50 mmol) was added at room temperature, and the mixture was stirredfor 1 hour. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, a colorlessgummy compound 43G was obtained.

Seventh Step

To compound 43G obtained in the sixth step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 27 mg of compound 43 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 4.26 (1H, d, J=10.9 Hz), 4.35 (1H, d,J=13.3 Hz), 4.58 (1H, dd, J=13.8, 3.5 Hz), 5.06 (1H, d, J=10.9 Hz), 7.36(10H, m), 8.36 (1H, s), 12.58 (1H, s), 15.62 (1H, s).

MS: m/z=405 [M+H]⁺.

Example 44

According to Example 43, compound 44 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 4.19 (2H, m), 4.42 (1H, dd, J=13.3, 3.8 Hz), 4.90(1H, d, J=9.2 Hz), 7.17-7.41 (10H, m), 8.40 (1H, s), 9.66 (1H, s), 12.70(1H, s), 15.60 (1H, s).

MS: m/z=391 [M+H]⁺.

Example 45

According to Example 43, compound 45 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.17-2.26 (1H, m), 3.22 (3H, s), 3.39 (2H, m),3.58-3.67 (1H, m), 4.19 (1H, d, J=10.7 Hz), 4.38 (2H, m), 4.95 (1H, d,J=10.8 Hz), 7.20-7.44 (10H, m), 8.28 (1H, s), 12.40 (1H, s), 15.60 (1H,s).

MS: m/z=449 [M+H]⁺.

Example 46

First Step

Compound 43E (289 mg, 0.584 mmol) obtained in Example 35 was dissolvedin THF (3 ml) and methanol (3 ml), a 2N aqueous sodium hydroxidesolution (1.46 ml, 2.92 mmol) was added at room temperature, and themixture was stirred for 1.5 hours. After 1N hydrochloric acid was added,and the mixture was extracted with ethyl acetate, the extract was driedwith sodium sulfate. After the solvent was distilled off, 342 mg ofcompound 46A was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.72-4.04 (3H, m), 4.46 (1H, m), 5.39 (1H, d, J=10.4Hz), 5.44 (1H, d, J=10.4 Hz), 6.04 (1H, brs), 7.19-7.60 (15H, m), 8.10(1H, s).

Second Step

Compound 46A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95:5→92:8, v/v) to obtain 85 mg of compound 46B as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 3.86 (3H, m), 4.45 (1H, m), 5.35 (1H, d, J=10.5 Hz),5.41 (1H, d, J=10.4 Hz), 5.94 (1H, brs), 6.48 (1H, d, J=7.4 Hz), 7.00(1H, d, J=7.4 Hz), 7.25-7.44 (13H, m), 7.62 (2H, m).

Third Step

Compound 46B (39 mg, 0.089 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (145 mg, 0.445 mmol) was added. After stirring at roomtemperature for 30 minutes, 1-bromo-2-methoxyethane (0.033 ml, 0.36mmol) was added, and the mixture was stirred at room temperature for 3.5hours. After the reaction solution was poured into water, and themixture was extracted with ethyl acetate, the extract was dried withsodium sulfate. After the solvent was distilled off under reducedpressure, the resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 97:3→95:5→92:8, v/v) to obtain 66mg of compound 46C as a colorless gummy substance.

Fourth Step

To compound 46C obtained in the third step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 21 mg of compound 46 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.12-2.21 (1H, m), 3.20 (3H, s), 3.55-3.64 (3H, m),3.81 (1H, d, J=13.0 Hz), 3.99 (1H, d, J=11.0 Hz), 4.22 (1H, dd, J=13.3,3.1 Hz), 4.86 (1H, d, J=11.0 Hz), 6.11 (1H, d, J=7.2 Hz), 7.18-7.45(11H, m).

MS: m/z=405 [M+H]⁺.

Example 47

According to Example 46, compound 47 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.70 (1H, d, J=12.2 Hz), 4.02 (1H, d, J 10.7 Hz),4.17 (1H, dd, J=13.2, 3.6 Hz), 4.79 (1H, t, J=3.4 Hz), 6.11 (1H, d,J=7.3 Hz), 7.18-7.44 (11H, m), 9.23 (1H, d, J=4.3 Hz).

MS: m/z=347 [M+H]⁺.

Example 48

First Step

Compound 41A (400 mg, 0.743 mmol) was dissolved in DMF (5 ml),triethylamine (0.21 ml, 1.5 mmol) and ethyl chloroformate (0.143 ml,1.49 mmol) were added at 0° C., and the mixture was stirred for 20minutes. Sodium borohydride (70.2 mg, 1.86 mmol) was added at 0° C., andthe mixture was stirred at room temperature for 30 minutes. Sodiumborohydride (70.2 mg, 1.86 mmol) was further added at 0° C., and themixture was stirred at room temperature for 2 hours. The reactionsolution was poured into water, the mixture was extracted with ethylacetate, and the extract was dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 97.3, v/v) to obtain 160 mg of compound 48A as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.19 (3H, s), 3.37-3.54 (3H, m), 3.65-3.73 (1H, m),3.87 (1H, m), 4.06 (2H, d, J=13.9 Hz), 4.31 (1H, d, J=11.2 Hz), 4.39(1H, d, J=13.8 Hz), 4.77 (1H, d, J=11.2 Hz), 5.36 (1H, d, J=10.1 Hz),5.41 (1H, d, J=10.1 Hz), 6.65 (1H, brs), 7.00 (2H, m), 7.19 (3H, m),7.33-7.49 (8H, m), 7.70 (2H, m).

Second Step

To compound 48A (50 mg, 0.095 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, the mixture was extractedwith chloroform, and the extract was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, chroloform-ethyl etherwere added, and the precipitated solid was filtered to obtain 3.5 mg ofcompound 48 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.51 (5H, m), 3.71 (1H, d, J=13.7 Hz),4.02 (1H, d, J=9.9 Hz), 4.09 (1H, d, J=12.0 Hz), 4.36 (1H, d, J=11.6Hz), 4.73 (1H, brs), 5.45 (1H, d, J=12.5 Hz), 7.00 (1H, s), 7.15 (5H,m), 7.28 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=7.5 Hz), 7.59 (2H, d, J=7.6Hz).

MS: m/z=435 [M+H]⁺.

Example 49

First Step

To Dess-Martin Periodinane (0.3M, methylene chloride solution, 52.0 ml,15.6 mmol) was added dropwise a methylene chloride solution (20 ml) ofcompound 49A (2.97 g, 10.4 mmol) at 0° C. After stirring at roomtemperature for 3 hours, the reaction mixture was poured into a 1Naqueous sodium hydroxide solution, and the mixture was extracted withethyl ether. The organic layer was washed with a 1N aqueous sodiumhydroxide solution and an aqueous saturated sodium chloride solution,and dried with magnesium sulfate. After the solvent was distilled offunder reduced pressure, 2.08 g of compound 49B was obtained as a whitesolid.

¹H-NMR (CDCl₃) δ: 3.13 (2H, d, J=6.6 Hz), 4.53 (1H, q, J=6.7 Hz), 5.12(2H, s), 5.28 (1H, brs), 7.26 (10H, m), 9.64 (1H, s).

Second Step

Compound 49B (700 mg, 2.47 mmol), 2-aminoethanol (166 mg, 2.72 mmol) andsodium sulfate (1.76 g, 12.4 mmol) were added to toluene (20 ml), andthe mixture was stirred at room temperature for 1 hour. Boc₂O (0.631 ml,2.72 mmol) was added at room temperature, and the mixture was stirredfor 18 hours. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 893 mg of 49C as a colorless gummy substance.

Third Step

Compound 49C (890 mg, 2.09 mmol) and palladium-active carbon (10% wet,200 mg) were added to ethanol (20 ml), and the mixture was stirred atroom temperature for 2 hours under hydrogen atmosphere. After filtrationwith celite, the solvent was concentrated under reduced pressure toobtain 656 mg of a colorless oily substance 49D.

¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 2.65-2.86 (2H, m), 3.32 (2H, m), 3.80(2H, m), 4.03-4.12 (1H, m), 4.86 (1H, brs), 7.22 (5H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (610 mg, 2.09mmol) and 49D (664 mg, 2.09 mmol) were added to toluene (6 ml), and themixture was stirred at 100° C. for 4 hours. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 884 mg of compound 49E as a pale yellow gummysubstance.

MS: m/z=593 [M+H]⁺.

Fifth Step

To compound 49E (860 mg, 1.45 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml). After stirring at room temperature for 30 minutes, thesolvent was distilled off under reduced pressure. Subsequently, toluene(10 ml) and 2-aminoethanol (0.175 ml, 2.90 mmol) were added, and themixture was stirred at 80° C. for 30 minutes. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,99:1→95:5→90:0, v/v) to obtain 157 mg of compound 49F as a colorlessgummy substance and 217 mg of compound 49G as a yellow solid.

49F: ¹H-NMR (CDCl₃) δ: 2.48 (1H, dd, J=14.0, 11.4 Hz), 3.22 (1H, dd,J=14.1, 3.3 Hz), 3.69 (1H, m), 3.77 (3H, s), 3.83-3.95 (1H, m), 4.08(1H, m), 4.29 (1H, m), 4.41 (1H, m), 5.34 (2H, m), 5.48 (1H, d, J=10.1Hz), 6.86 (2H, m), 7.20-7.39 (7H, m), 7.64 (2H, m)

49G: ¹H-NMR (DMSO-d₆) δ: 3.70 (2H, t, J=5.3 Hz), 3.73 (3H, s), 3.86 (2H,t, J=5.3 Hz), 4.14 (2H, s), 4.98 (1H, t, J=5.0 Hz), 5.06 (2H, s), 6.98(1H, s), 7.35 (8H, m), 7.62 (2H, d, J=7.1 Hz), 8.34 (1H, d, J=0.8 Hz).

Sixth Step

The compound 49G (214 mg, 0.465 mmol) was dissolved in THF (4 ml),ethanol (2 ml) and methylene chloride (2 ml), a 2N aqueous sodiumhydroxide solution (1.16 ml, 2.32 mmol) was added at room temperature,and the mixture was stirred for 2.5 hours. After 1N hydrochloric acidwas added, and the mixture was extracted with chloroform, the extractwas dried with sodium sulfate. After the solvent was distilled off underreduced pressure, 158 mg of compound 49H was obtained as a yellow solid.

¹H-NMR (DMSO-d₆) δ: 3.70 (2H, q, J=5.2 Hz), 3.89 (2H, t, J=5.3 Hz), 4.22(2H, s), 4.97 (1H, t, J=5.6 Hz), 5.12 (2H, s), 7.23-7.41 (9H, m), 7.60(2H, m), 8.54 (1H, s).

Seventh Step

Compound 49H (50.0 mg, 0.112 mmol) and palladium-active carbon (10%,wet, 12 mg) were added to methanol (1 ml) and DMF (3 ml), and themixture was stirred at room temperature for 5 hours under hydrogenatmosphere. After filtration with celite, the solvent was concentratedunder reduced pressure, chloroform-methanol-ethyl ether were added, andthe precipitated solid was filtered to obtain 9.0 mg of compound 49 as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 3.10 (2H, m), 3.51-3.69 (4H, m), 4.10 (1H, d, J=10.7Hz), 4.94 (2H, m), 7.11-7.26 (5H, m), 8.03 (1H, s), 12.94 (1H, brs),15.30 (1H, brs).

MS: m/z=359 [M+H]⁺.

Example 50

First Step

Compound 50A (1.00 g, 3.98 mmol), triphenylphosphine (1.15 g, 4.48 mmol)and N-methyl-2-nitrobenzenesulfonamide (860 mg, 3.98 mmol) were added toTHF (10 ml), diethyl azodicarboxylate (2.2M in toluene, 1.99 ml, 4.38mmol) was added dropwise at room temperature. After stirring at roomtemperature for 3 hours, and the solvent was distilled off under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (n-hexane-ethyl acetate, 1;1, v/v) to obtain 710 mg ofcompound 50B as a colorless gummy substance.

Second Step

Compound 50B (458 mg, 1.02 mmol) was dissolved in acetonitrile,potassium carbonate (422 mg, 3.06 mmol) and benzenethiol (0.126 ml, 1.22mmol) were added, and the mixture was stirred at room temperature for 5hours. The reaction solution was poured into a 1N aqueous sodiumhydroxide solution, the mixture was extracted with methylene chloride,and the extract was dried with sodium sulfate. The resulting crudeproduct was purified by amino column chromatography(chloroform-methanol, 95:5, v/v) to obtain 147 mg of compound 50C as acolorless oily substance.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 2.40 (3H, s), 2.51-2.89 (4H, m), 3.90(1H, s), 4.69 (1H, s), 7.17-7.31 (5H, m).

Third Step

Compound 50C (140 mg, 0.530 mmol) and3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (WO 2006/116764, 119 mg,0.482 mmol) were added to THF (3 ml),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg,0.578 mmol) and 1-hydroxybenzotriazole (65.1 mg, 0.482 mmol) were added,and the mixture was stirred at room temperature for 18 hours. Thereaction solution was poured into sodium bicarbonate water, the mixturewas extracted with ethyl acetate, and the extract was dried with sodiumsulfate. The resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 97;3, v/v) to obtain 219 mg ofcompound 50D as a colorless solid.

MS: m/z=493 [M+H]⁺.

Fourth Step

To compound 50D (216 mg, 0.439 mmol) was added 4N HCl (ethyl acetatesolution, 3 ml). After the mixture was stirred at room temperature for 1hour, the solvent was distilled off under reduced pressure.Subsequently, ethanol (4 ml) and an aqueous saturated sodium carbonatesolution (3 ml) were added, and the mixture was stirred at 60° C. for 2hours. After water was added, and the mixture was extracted with ethylacetate, the extract was dried with sodium sulfate. The resulting crudeproduct was purified by amino column chromatography(chloroform-methanol, 95;5, v/v) to obtain 108 mg of compound 50E as apale yellow gummy substance.

¹H-NMR (CDCl₃) δ: 3.00 (2H, m), 3.13 (3H, s), 3.18 (1H, m), 3.88 (1H,dd, J=13.5, 3.4 Hz), 4.00-4.07 (1H, m), 5.26 (1H, d, J=10.2 Hz), 5.46(1H, d, J=10.1 Hz), 6.25 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz),6.99-7.02 (2H, m), 7.28-7.37 (6H, m), 7.63-7.67 (2H, m).

Fifth Step

To compound 50E (105 mg, 0.280 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 30 minutes.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-methanol-ethyl ether were added, and the precipitatedsolid was filtered to obtain 29 mg of compound 50 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.99 (3H, s), 3.26-3.47 (3H, m), 4.07 (1H, d, J=11.1Hz), 4.80 (1H, m), 6.43 (1H, d, J=6.9 Hz), 7.11-7.29 (5H, m), 7.50 (1H,d, J=6.9 Hz).

MS: m/z=285 [M+H]⁺.

Example 51

First Step

Compound 1D (60 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Thereaction solution was distilled off, and the resulting residue waspurified by LC/MS to obtain compound 51 (43 mg, 0.09 mmol).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=6.9 Hz), 3.11 (3H, s), 3.48-3.58 (2H,m), 3.95-4.12 (3H, m), 4.40 (1H, d, J=11.4 Hz), 5.59 (1H, d, J=11.4 Hz),7.11 (1H, d, J=7.3 Hz), 7.17 (2H, t, J=7.2 Hz), 7.26 (2H, d, J=7.1 Hz),7.30 (1H, t, J=7.3 Hz), 7.42 (2H, t, J=7.2 Hz), 7.60 (3H, m), 12.55 (1H,brs).

MS: m/z=477.2 [M+H]⁺.

Example 52

First Step

To a DMF (10 ml) solution of compound 1I (2.0 g, 4.32 mmol) were addedWSC HCl (1.24 g, 6.49 mmol) and HOBt (876.9 mg, 6.49 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 1hour. To the reaction solution were added O,N-dimethylhydroxylaminehydrochloride (842.7 mg, 8.64 mmol) and triethylamine (2.19 g, 21.6mmol), the mixture was stirred at the same temperature for 3 hours,thereafter, water was added, and the mixture was extracted with ethylacetate three times. After the extract was washed with water threetimes, and dried with sodium sulfate, the solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (7;3, v/v)and, then, with only ethyl acetate. Concentration of an objectivefraction afforded 543 mg (yield 25%) of compound 52A as an oil.

MS: m/z=506 [M+H]⁺.

Second Step

A THF (5 ml) solution of compound 52A (543 mg, 1.07 mmol) was cooled to−78° C., a methylmagnesium bromide 0.97M THF solution (1.66 ml, 1.61mmol) was added, and temperature was raised up to −20° C. over 2 hours.To the reaction solution was added 1N hydrochloric acid, and the mixturewas extracted with ethyl acetate three times. After the extract wasdried with sodium sulfate, the solvent was distilled off, and theresulting oil was purified by silica gel chromatography. The materialswere eluted firstly with n-hexane-ethyl acetate (7:3, v/v) and, then,with only ethyl acetate. Concentration of an objective fraction afforded256.8 mg (yield 52%) of compound 52B as an oil.

¹H-NMR (CDCl₃) δ: 2.65 (3H, s), 3.08 (2H, d, J=7.5 Hz), 3.12 (3H, s),3.53-3.68 (4H, m), 3.79-3.95 (1H, m), 3.92 (1H, dd, J=3.3 Hz, 13.5 Hz),4.10-4.16 (1H, m), 5.30 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz),6.99-7.02 (2H, m), 7.25-7.38 (6H, m), 7.49 (1H, s), 7.63-7.66 (2H, m).

Third Step

To a dichloromethane (4 ml) solution of compound 52B (256 mg, 0.558mmol) was added mCPBA (144.3 mg, 0.836 mmol) under ice-cooling, and themixture was stirred at room temperature for 2 hours. To the reactionsolution was added an aqueous sodium thiosulfate solution, and themixture was extracted with ethyl acetate three times. After the extractwas washed with saturated sodium bicarbonate water two times, and driedwith sodium sulfate, the solvent was distilled off, the resulting oilwas dissolved in ethanol (4 ml), and a 2N-aqueous sodium hydroxidesolution (1 ml) was added, followed by refluxing for 1 hour. After thesolvent was distilled off, the precipitated solid was washed withdiisopropyl ether to obtain 242 mg (yield 100%) of compound 52C.

¹H-NMR (CDCl₃) δ: 3.09 (2H, d, J=6.9 Hz), 3.32 (3H, s), 3.54 (1H, d,J=14.1 Hz), 3.59-3.71 (2H, m), 3.76-3.85 (1H, m), 3.92 (1H, dd, J=3.6Hz, 13.5 Hz), 4.03 (1H, brt), 5.28 (1H, d, J=10.2 Hz), 5.47 (1H, d,J=10.2 Hz), 6.68 (1H, s), 7.00-7.04 (2H, m), 7.23-7.37 (6H, m), 7.64(2H, d, J=6.3 Hz).

Fourth Step

To a THF (3 ml) solution of compound 52C (242 mg, 0.558 mmol) was added10% Pd-C (50 mg), and the mixture was subjected to a catalytic reductionunder hydrogen stream. The catalyst was removed by filtration, and thefiltrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 60mg (yield 31%) of compound 52.

¹H-NMR (CDCl₃) δ: 3.05 (2H, brs), 3.36 (3H, s), 3.58 (1H, d, J=12 Hz),3.66-3.68 (2H, m), 3.74-3.75 (2H, m), 4.11-4.19 (2H, m), 6.80 (1H, brs),6.90-7.04 (2H, m), 7.30 (3H, brs).

Example 53

First Step

To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol) were addedtriethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg,6.69 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 10 minutes. To the reaction solution were addedmethanesulfonamide (1.06 g, 11.15 mmol) and DMAP (272.4 mg, 2.23 mmol),and the mixture was heated to stir at 80° C. for 2 hours. To thereaction solution was added water, and the mixture was extracted withethyl acetate three times. After the extract was washed with water threetimes, and dried with sodium sulfate, the solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with only chloroform and, then, withchloroform-MeOH (9;1, v/v). Concentration of an objective fractionafforded 535 mg (yield 46%) of compound 53A as an oil.

MS: m/z=463 [M+H]⁺.

Second Step

To a THF (5 ml) solution of compound 53A (535 mg, 0.991 mmol) was added10% Pd-C (218 mg), and the mixture was subjected to a catalyticreduction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 235mg (yield 53%) of compound 53.

¹H-NMR (DMSO-d₆) δ: 2.99-3.17 (2H, m), 3.27 (3H, s), 3.33 (3H, s),3.53-3.76 (5H, m), 4.06 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.98 (1H, brs),7.14 (2H, d, J=6.6 Hz), 7.19-7.30 (3H, m), 8.07 (1H, s), 12.84 (1H, s),13.24 (1H, s).

Example 54

First Step

To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol) were addedtriethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg,6.69 mmol) under ice-cooling, and the mixture was stirred at the sametemperature for 10 minutes. The reaction solution was added dropwise toan ice-cooled solution of sodium borohydride (441 mg, 11.7 mmol) inwater (5 ml), and the mixture was stirred at the same temperature for 2hours. To the reaction solution was added 2N hydrochloric acid to stopthe reaction, and the mixture was neutralized with a 2N aqueous sodiumhydroxide solution, and extracted with ethyl acetate three times. Afterthe extract was washed with water three times, and dried with sodiumsulfate, the solvent was distilled off, and the resulting crude productwas dissolved in dichloromethane (5 ml).

To the dichloromethane solution was added manganese dioxide (2.1 g,24.15 mmol), and the mixture was stirred at room temperature for 6hours. After the reaction solution was filtered, and the solvent wasdistilled off, the resulting oil was purified by silica gelchromatography. Elution with ethyl acetate-MeOH (9;1, v/v) andconcentration of an objective fraction afforded 188 mg (yield 19%) ofcompound 54A.

MS: m/z=447 [M+H]⁺.

Second Step

Compound 54A (188 mg, 0.422 mmol) was dissolved in THF (6 ml), 28%aqueous ammonia and iodine (117.7 mg, 0.464 mmol) were added at roomtemperature, and the mixture was stirred at the same temperature for 2hours. To the reaction solution was added an aqueous sodium thiosulfatesolution, and the mixture was extracted with ethyl acetate three times.After the extract was dried with sodium sulfate, the solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. Elution with ethyl acetate-MeOH (9:1, v/v) andconcentration of an objective fraction afforded 54.7 mg (yield 29%) ofcompound 54B.

¹H-NMR (CDCl₃) δ: 3.05 (2H, d, J=7.5 Hz), 3.33 (3H, s), 3.56-3.79 (5H,m), 3.99 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.08 (1H, brt), 5.33 (1H, d,J=10.2 Hz), 5.46 (1H, d, J=10.2 Hz), 6.83 (1H, s), 6.93-6.97 (2H, m),7.25-7.37 (5H, m), 7.58-7.62 (2H, m).

Third Step

To a toluene (2 ml) solution of compound 54B (216 mg, 0.487 mmol) wereadded sodium azide (95 mg, 1.46 mmol) and triethylamine (201 mg, 1.46mmol), and the mixture was stirred at room temperature for 6 hours. Thereaction solution was extracted with a 2N aqueous sodium hydroxidesolution two times, and the extract was neutralized with 2N hydrochloricacid, and extracted with ethyl acetate three times. After drying of theorganic layer with sodium sulfate, the solvent was distilled off toobtain 65 mg (yield 27%) of compound 54C.

¹H-NMR (CDCl₃) δ: 3.08-3.21 (2H, m), 3.33 (3H, s), 3.55-3.70 (4H, m),3.81-3.90 (1H, m), 3.96-4, 01 (1H, m), 4.51 (1H, brt), 5.31 (1H, d,J=10.2 Hz), 5.42 (1H, d, J=10.2 Hz), 7.03-7.05 (2H, m), 7.18-7.37 (6H,m), 7.58-7.61 (2H, m), 8.33 (1H, s).

Fourth Step

To a THF (2 ml)-MeOH (2 ml) solution of compound 54C (500 mg, 1.03 mmol)was added 10% Pd-C (100 mg), and the mixture was subjected to acatalytic reduction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. The resulting residue wasdissolved in dichloromethane (10 ml), and the solution was extractedwith a 2N aqueous sodium hydroxide solution two times. After the extractwas neutralized with 2N hydrochloric acid, the mixture was extractedwith ethyl acetate three times. The organic layer was dried with sodiumsulfate, the solvent was distilled off, and the resulting solid waswashed with diisopropyl ether, and filtered to obtain 55 mg (yield 14%)of compound 54.

¹H-NMR (DMSO-d₆) δ: 3.01-3.19 (2H, m), 3.28 (3H, s), 3.51-3.79 (5H, m),4.09 (1H, dd, J=3.9 Hz, 13.5 Hz), 4.95 (1H, brs), 7.13-7.26 (5H, m),8.20 (1H, s), 12.23 (1H, s).

Example 55

First Step

To a THF (5 ml) solution of compound 1I (500 mg, 1.08 mmol) was added atrimethylsilyldiazomethane 2M hexane solution (1 ml, 2.0 mmol) at roomtemperature, and the mixture was heated to 50° C., and stirred. Afterthe solvent was distilled off, the resulting oil was purified by silicagel chromatography. Elution with n-hexane-ethyl acetate (1;1, v/v) andconcentration of objective fraction afforded 115 mg (yield 22%) ofcompound 55A.

¹H-NMR (CDCl₃) δ: 3.06 (2H, d, J=7.5 Hz), 3.31 (3H, s), 3.51-3.72 (5H,m), 3.81 (3H, s), 3.98 (1H, dd, J=3.6 Hz), 13.5 Hz), 4.11 (1H, brt),5.22 (1H, d, J=9.6 Hz), 5.46 (1H, d, J=9.6 Hz), 6.99-7.02 (2H, m),7.26-7.37 (6H, m), 7.46 (1H, s), 7.65-7.69 (2H, m).

Second Step

Compound 55A (210 mg, 0.441 mmol) was dissolved in THF (2 ml), 10% Pd-C(85.7 mg) was added, and the mixture was subjected to a catalyticreduction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. The resulting residue was washed withdiisopropyl ether to obtain 50 mg (yield 23%) of compound 55.

¹H-NMR (CDCl₃) δ: 1.55 (2H, d, J=7.5 Hz), 3.37 (3H, s), 3.59-3.84 (5H,m), 4.23-4.32 (2H, m), 7.00 (2H, dd, J=1.5 Hz, 6.9 Hz), 7.23-7.32 (3H,m), 7.39 (1H, s), 12.31 (1H, brs).

Example 56

First Step

A DMF (5 ml) solution of compound 2D (424 mg, 0.787 mmol) wasice-cooled, and triethylamine (327 ul, 2.36 mmol) and, subsequently,ethyl chloroformate (150 ul, 1.57 mmol) were added. After the reactionsolution was stirred at room temperature for 10 minutes, it wasice-cooled again, sodium azide (154 mg, 2.36 mmol) was added, and themixture was stirred for 1 hour. To the reaction solution were addeddichloromethane, water and a small amount of methanol, thedichloromethane layer was separated, and the aqueous layer was extractedwith dichloromethane once. The combined extracts were concentrated,methanol (8 ml) was added to the resulting residue, the mixture wasstirred at 50° C. for 3 hours, and the solvent was distilled off. Theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v)and, then, with only ethyl acetate. Concentration of objective fractionafforded 160 mg of compound 56A as a white solid.

¹H-NMR (CDCl₃) δ: 3.08-3.18 (4H, m), 3.35-3.49 (3H, m), 3.68 (3H, s),3.98 (2H, dt, J=23.1, 5.6 Hz), 4.32 (1H, d, J=11.3 Hz), 4.59 (1H, d,J=11.3 Hz), 5.37 (2H, dd, J=12.0, 10.4 Hz), 6.98-7.70 (15H, m).

MS: m/z=568.25 [M+H]⁺.

Second Step

Compound 56A (160 mg, 0.102 mmol) was dissolved in EtOH (10 mL), a 2Naqueous sodium hydroxide solution (14 ml) was added, and the mixture wasstirred at 60° C. for 2 hours. After the reaction solution wasconcentrated under reduced pressure, the residue was distributed betweendichloromethane and water. The dichloromethane layer was separated, andthe aqueous layer was extracted with dichloromethane three times. Thesolvent was distilled off to obtain compound 56B.

¹H-NMR (CDCl₃) δ: 2.97-3.06 (1H, m), 3.15 (3H, s), 3.38-3.44 (3H, m),3.71 (2H, s), 3.93-3.99 (2H, m), 4.35 (2H, dd, J=19.3, 11.1 Hz), 5.37(2H, dd, J=31.6, 10.1 Hz), 6.04 (1H, s), 6.98 (2H, dd, J=6.4, 2.9 Hz),7.17 (4H, t, J=3.3 Hz), 7.28-7.69 (12H, m).

MS: m/z=509.23 [M+H]⁺.

Third Step

Compound 56B (56 mg, 0.11 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas subjected to toluene azeotropy, and the resulting residue waspurified using a LCMS fractionation device. The eluted solvent wasdistilled off, isopropyl ether was added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether and dryingafforded 7 mg of compound 56.

MS: m/z=420.07 [M+H]⁺.

Example 57

First Step

To a THF (1 mL) solution of compound 56B (25 mg, 0.049 mmol) were addedtriethylamine (20 ul, 0.015 mmol) and, subsequently, acetic acidanhydride (7.0 ul, 0.074 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 15 minutes. Then, 4-fluorobenzyl amine(330 mg, 1.75 mmol) was added, and the mixture was stirred for 7 hours.Further, triethylamine (20 uL, 0.15 mmol) and, subsequently, acetic acidanhydride (7.0 ul, 0.074 mmol) were added, and the mixture was stirredovernight. To the reaction solution were added water, ethyl acetate, andbrine, the ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. To the combined extracts was added sodiumsulfate, and filtration and concentration afforded 18 mg of compound 57Aas a white solid.

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 3.09-3.14 (4H, m), 3.41-3.45 (3H, m),3.95-4.02 (2H, m), 4.31 (1H, d, J=11.4 Hz), 4.59 (1H, d, J=12.4 Hz),5.36 (2H, s), 7.00 (2H, d, J=4.0 Hz), 7.11-7.16 (3H, m), 7.36 (7H, tt,J=14.5, 5.1 Hz), 7.62 (2H, t, J=7.3 Hz), 8.02 (1H, s), 8.18 (1H, s).

MS: m/z=552.20 [M+H]⁺.

Second Step

Compound 57A (21 mg, 0.038 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 3.5 hours. The reactionmixture was subjected to toluene azeotropy, isopropyl ether was added tothe resulting residue, and the precipitated solid was filtered. Washingwith isopropyl ether, and drying afforded 10 mg of compound 57.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 3.20 (3H, s), 3.39-3.60 (4H, m),3.76-3.86 (1H, m), 4.08 (1H, dd, J=13.7, 3.7 Hz), 4.31 (1H, d, J=11.5Hz), 4.68 (1H, dd, J=8.5, 4.3 Hz), 6.96-7.19 (4H, m), 7.30-7.44 (6H, m),8.11 (1H, s).

MS: m/z=462.20 [M+H]⁺.

Example 58

According to Example 57, compound 58 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 3.20 (3H, s), 3.41-3.54 (3H, m), 3.60-3.68 (2H, m),3.73-3.85 (1H, m), 4.12 (1H, dt, J=14.0, 3.5 Hz), 4.31 (1H, d, J=11.4Hz), 4.68 (1H, dd, J=11.4, 2.6 Hz), 6.95-7.21 (5H, m), 7.39 (5H, dt,J=26.9, 7.6 Hz), 7.94 (1H, s), 8.88 (1H, s).

MS: m/z=516.10 [M+H]⁺.

Example 59

According to Example 57, compound 59 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 3.21 (3H, s), 3.43-3.63 (4H, m), 3.82 (1H, d, J=14.0Hz), 4.12 (1H, dd, J=8.3, 4.2 Hz), 4.35 (1H, d, J=11.2 Hz), 4.74 (1H, d,J=8.3 Hz), 6.90-7.18 (5H, m), 7.34-7.60 (8H, m), 7.82 (2H, d, J=6.8 Hz),8.34 (1H, s), 8.89 (1H, s).

MS: m/z=523.21 [M+H]⁺.

Example 60

To compound 56B (30 mg, 0.059 mmol) were added formic acid (1.0 mL, 26mmol) and, subsequently, a 37% formaldehyde solution (0.5 mL, 6.7 mmol),and the mixture was stirred at 100° C. for 7 hours. The reactionsolution was subjected to toluene azeotropy, DMSO was added, insolubleswere filtered and, thereafter, purification was performed using a LCMSfractionating device. The eluted solvent was distilled off, isopropylether was added to the residue, and the precipitated solid was filtered.Washing with isopropyl ether, and drying afforded 3 mg of compound 60.

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 3.18 (3H, s), 3.29-3.66 (4H, m), 3.82(1H, d, J=12.5 Hz), 4.06-4.15 (1H, m), 4.31 (1H, d, J=11.7 Hz), 4.54(1H, d, J=8.1 Hz), 5.97 (1H, s), 7.01 (2H, dd, J=6.4, 2.8 Hz), 7.17 (3H,t, J=2.9 Hz), 7.32-7.45 (6H, m).

MS: m/z=448.15 [M+H]⁺.

Example 61

First Step

Compound 56B (50 mg, 0.098 mmol) was dissolved in THF (1 mL), Boc₂O(0.068 mL, 0.29 mmol) and, subsequently, DMAP (6.0 mg, 0.049 mmol) wereadded, and the mixture was stirred at room temperature for 5 hours. Tothe reaction solution were added water and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 20 mg of compound 61A as a colorlesstransparent oil.

MS: m/z=610.50 [M+H]⁺.

Second Step

Compound 61A (20 mg, 0.033 mmol) was dissolved in DMF (1 mL), sodiumhydride (2.6 mg, 0.066 mmol) was added under ice-cooling, the mixturewas stirred for 10 minutes, methyl iodide (4.1 uL, 0.066 mmol) wasadded, and the mixture was stirred at room temperature for 1.5 hours.Ice water, ethyl acetate and brine were added, the ethyl acetate layerwas separated, and the aqueous layer was extracted with ethyl acetate.To the combined extracts was added sodium sulfate, the mixture wasfiltered, and the solvent was distilled off. The resulting residue waspurified by silica gel column chromatography. Concentration of anobjective fraction afforded 13 mg of compound 61B as a white solid.

MS: m/z=624.25 [M+H]⁺.

Third Step

Compound 61B (13 mg, 0.021 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using a LCMS fractionating device. The eluted solvent wasdistilled off, isopropyl ether-hexane were added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether, anddrying afforded 7.5 mg of compound 61.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 3.26 (3H, s), 3.46-3.70 (4H, m), 4.23(1H, d, J=11.0 Hz), 4.58-4.60 (1H, br m), 5.41-5.44 (1H, br m), 6.28(1H, br s), 6.99 (2H, br s), 7.13 (3H, br s), 7.31-7.46 (6H, m).

MS: m/z=434.10 [M+H]⁺.

Example 62

First Step

Compound 2D (112 mg, 0.208 mmol) was dissolved in DMF (2 mL),triethylamine (0.144 ml, 1.04 mmol) and, subsequently, ethylchloroformate (0.040 mL, 0.42 mmol) were added under ice-cooling, themixture was stirred at room temperature for 10 minutes, thereafter,N,O-dimethylhydroxyamine hydrochloride (41 mg, 0.42 mmol) and,subsequently, DMAP (3 mg, 0.02 mmol) were added, and the mixture wasstirred at room temperature for 1 hour. To the reaction solution wereadded water, and ethyl acetate, the ethyl acetate layer was separated,and the aqueous layer was extracted with ethyl acetate. To the combinedextracts was added sodium sulfate, the mixture was filtered, and thesolvent was distilled off. The resulting residue was purified by silicagel column chromatography. Concentration of an objective fractionafforded 127 mg of crude purified product 62A as a yellow oil.

MS: m/z=582.20 [M+H]⁺.

Second Step

Compound 62A (137 mg, 0.236 mmol) was dissolved in THF (8 mL), a 2M THFsolution of methylmagnesium bromide (0.444 ml, 0.471 mmol) was added at−78° C. under nitrogen stream, and the mixture was stirred for 30minutes while temperature was raised to −50° C. To the reaction solutionwas added IM hydrochloric acid (4 ml), the mixture was stirred at 0° C.for 20 minutes, ethyl acetate was added, the ethyl acetate layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were neutralized with an aqueous saturated sodiumbicarbonate solution, sodium sulfate was added to the organic layer, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 67 mg of compound 62B as a yellow oil.

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.01-3.14 (1H, m), 3.16 (3H, s),3.37-3.54 (3H, m), 3.91-4.07 (2H, m), 4.28 (1H, d, J=11.3 Hz), 4.50-4.60(1H, m), 5.42 (2H, d, J=1.2 Hz), 6.97-6.99 (2H, m), 7.14-7.17 (4H, m),7.31-7.45 (8H, m), 7.65 (2H, d, J=6.5 Hz).

MS: m/z=537.20 [M+H]⁺.

Third Step

Compound 62B (67 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL),mCPBA (32 mg, 0.19 mmol) was added at 0° C. under nitrogen stream, andthe mixture was stirred at room temperature for 3 hours. The reactionsolution was ice-cooled, an aqueous sodium thiosulfate solution, andethyl acetate were added, the ethyl acetate layer was separated, and theaqueous layer was extracted with ethyl acetate. The combined extractswere neutralized with an aqueous saturated sodium bicarbonate solution,sodium sulfate was added to the organic layer, the mixture was filtered,and the solvent was distilled off to obtain 64 mg of compound 62C.

MS: m/z=553.23 [M+H]⁺.

Fourth Step

Compound 62C (64 mg, 0.12 mmol) was dissolved in ethanol (8 mL), and thesolution was heated to reflux for 4 hours. The reaction solution wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography. Concentration of an objective fraction afforded42 mg of compound 62D.

¹H-NMR (CDCl₃) δ: 2.93-3.09 (1H, m), 3.16 (3H, s), 3.33-3.53 (4H, m),3.90-4.07 (2H, m), 4.29-4.47 (2H, m), 5.41 (2H, q, J=10.4 Hz), 6.34 (1H,s), 6.95-6.99 (2H, m), 7.12-7.21 (4H, m), 7.33-7.42 (8H, m), 7.64 (2H,d, J=6.9 Hz).

MS: m/z=511.21 [M+H]⁺.

Fifth Step

Compound 62D (41 mg, 0.080 mmol) was dissolved in DMF (1 mL), sodiumhydride (6.4 mg, 0.16 mmol) was added under ice-cooling, the mixture wasstirred for 10 minutes, methyl iodide (0.010 ml, 0.16 mmol) was added,and the mixture was stirred at room temperature for 1.5 hours. To thereaction solution were added ice water and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 41 mg of compound 62E as a whitesolid.

¹H-NMR (CDCl₃) δ: 2.99-3.09 (1H, m), 3.16 (3H, s), 3.25 (3H, s),3.32-3.38 (1H, m), 3.42-3.50 (2H, m), 3.94-4.03 (2H, m), 4.28 (1H, d,J=11.3 Hz), 4.43 (1H, br s), 5.40 (2H, dd, J=28.3, 10.2 Hz), 6.01 (1H,s), 6.90-7.19 (5H, m), 7.28-7.44 (8H, m), 7.66 (2H, d, J=6.4 Hz).

MS: m/z=525.21 [M+H]⁺.

Sixth Step

Compound 62E (40 mg, 0.076 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using a LCMS fractionating device. The eluted solvent wasdistilled off, ethyl acetate-isopropyl ether-hexane were added to theresidue, and the precipitated solid was filtered. Washing with isopropylether, and drying afforded 7.1 mg of compound 62 as a pink solid.

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.22 (3H, s), 3.40-3.53 (4H, m),3.63-3.71 (1H, m), 4.24 (1H, d, J=11.5 Hz), 4.45 (1H, d, J=13.3 Hz),4.60 (1H, d, J=11.2 Hz), 6.08 (1H, d, J=11.7 Hz), 6.96-6.99 (2H, br m),7.13-7.17 (3H, m), 7.30-7.43 (5H, m).

MS: m/z=435.15 [M+H]⁺.

Example 63

First Step

Compound 2D (164 mg, 0.304 mmol) was dissolved in diphenyl ether (1 mL),the mixture was stirred at 245° C. for 1 hour using a microwaveapparatus and, thereafter, the reaction solution was purified by silicagel column chromatography. Concentration of an objective fractionafforded 72 mg of compound 63A as a brown solid.

¹H-NMR (CDCl₃) δ: 2.92-3.01 (1H, m), 3.16 (3H, s), 3.32-3.50 (3H, m),3.90-4.46 (4H, m), 5.42 (2H, dd, J=26.1, 10.3 Hz), 5.94 (1H, d, J=7.4Hz), 6.28 (1H, d, J=7.5 Hz), 6.96-6.99 (2H, m), 7.15-7.19 (3H, m),7.28-7.44 (8H, m), 7.62-7.65 (2H, m).

MS: m/z=495.21 [M+H]⁺.

Second Step

To a dichloromethane (4 mL) solution of compound 63A (21 mg, 0.042 mmol)was added NBS (11 mg, 0.062 mmol), and the mixture was heated to refluxfor 1 hour. The reaction solution was allowed to cool, and purified bysilica gel column chromatography. Concentration of an objective fractionafforded 26 mg of compound 63B as a white solid.

¹H-NMR (CDCl₃) δ: 3.01-3.09 (1H, m), 3.16 (3H, s), 3.35-3.53 (3H, m),3.92-4.47 (4H, m), 5.41 (2H, dd, J=32.6, 10.0 Hz), 6.72 (1H, s),6.97-7.00 (2H, br m), 7.20-7.22 (3H, m), 7.30-7.46 (8H, m), 7.66-7.70(2H, m).

MS: m/z=573.20 [M+H]⁺.

Third Step

Compound 63B (10 mg, 0.017 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 50 minutes. The reactionmixture was subjected to toluene azeotropy, isopropyl ether was added tothe resulting residue, and the precipitated solid was filtered. Washingwith isopropyl ether, and drying afforded 1.4 mg of compound 63 as anorange solid.

MS: m/z=483.15 [M+H]⁺.

Example 64

First Step

To a DMF solution (2 mL) of compound 63B (20 mg, 0.035 mmol) were addedpyrazole-4-boronic acid pinacol ester (36 mg, 0.19 mmol) and,subsequently, potassium carbonate (29 mg, 0.21 mmol) and, thereafter,tetrakistriphenylphosphinepalladium (24 mg, 0.021 mmol) was added undernitrogen atmosphere, and the mixture was stirred at 110° C. for 8.5hours. After the reaction solution was concentrated, ethyl acetate andmethanol were added, and insolubles were removed. The filtrate wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography. Concentration of an objective fraction afforded18 mg of compound 64A as a white solid.

MS: m/z=561.30 [M+H]⁺.

Second Step

Compound 64A (14 mg, 0.025 mmol) was dissolved in TFA (2 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using a LCMS fractionating device. The eluted solvent wasdistilled off, isopropyl ether was added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether, anddrying afforded 1.1 mg of compound 64 as an orange solid.

MS: m/z=471.20 [M+H]⁺.

Example 65

First Step

A THF (1.1 L) solution of compound 65A (WO 2006/088173, 20.0 g, 69.6mmol) was retained at 25° C. on a water bath, an aqueous (378 mL)solution of sodium chlorite (25.2 g, 278 mmol) and amidosulfuric acid(27.0 g, 278 mmol) was added dropwise over 30 minutes. The reactionsolution was stirred at the same temperature for 1 hour, andconcentrated under reduced pressure. To the residue were added ice water(100 mL) and diethyl ether (100 mL), and the precipitated solid wasfiltered. The resulting crude purified product was washed with water anddiethyl ether to obtain 20.3 g of compound 65B as a white solid.

¹H-NMR (DMSO-d₆) δ: 3.74 (3H, s), 5.11 (2H, s), 7.31-7.38 (3H, m), 7.48(2H, d, J=7.2 Hz), 8.11 (1H, s), 12.07 (1H, brs).

Second Step

Compound 65B (2.0 g, 6.59 mmol) was dissolved in DMF (340 mL), HATU(2.76 g, 7.25 mmol), methylamine (2 mol/L, THF solution, 3.63 mL, 7.25mmol) and triethylamine (9.89 mmol) were added, and the mixture wasstirred at room temperature for 5 hours. The reaction solution wasdistributed between ethyl acetate and water, the ethyl acetate layer wasseparated. and the aqueous layer was extracted with ethyl acetate once.The combined extracts were washed with water and an aqueous saturatedsodium chloride solution, and dried. The solvent was distilled off toobtain 1.66 g of a crude purified product of compound 65C as a whitesolid.

¹H-NMR (DMSO-d₆) δ: 3.38 (3H, brs), 3.75 (3H, s), 5.37 (2H, s),7.34-7.44 (5H, m), 8.10 (1H, s), 8.38 (1H, s), 11.84 (1H, brs).

Third Step

To a DMF (20 mL) solution of compound 65C (1.2 g, 3.79 mmol) were addedpotassium carbonate (1.04 g, 7.59 mmol) andO-(2,4-dinitrophenyl)hydroxylamine (831 mg, 4.17 mmol), and the mixturewas stirred at room temperature for 3 hours. To the reaction solutionwas added water, and the precipitated solid was filtered, and washedwith water to obtain 1.0 g of a crude purified product of compound 65D.

¹H-NMR (DMSO-d₆) δ: 3.74 (3H, s), 3.83 (3H, brs), 5.05 (2H, s), 6.46(2H, brs), 7.31-7.38 (5H, m), 8.20 (1H, s), 8.52 (1H, brs).

Fourth Step

To a DMF (10 mL) solution of compound 65D (1.0 g, 3.02 mmol) were addedparaformaldehyde (109 mg, 3.62 mmol) and acetic acid (0.017 ml, 0.302mmol) at room temperature, and the mixture was stirred at 105° C. for 2hours. The reaction solution was cooled to 0° C., cesium carbonate (3.44g, 10.6 mmol) was added, and the mixture was stirred at room temperaturefor 1 hour. To the reaction solution was added water, and the mixturewas distributed between ethyl acetate and water. The organic layer waswashed with an aqueous saturated sodium chloride solution, and dried.The solvent was distilled off to obtain 120 mg of compound 65E.

MS: m/z=344 [M+H]⁺.

Fifth Step

To a DMF (1 mL) solution of compound 65E (17.0 mg, 0.05 mmol) were addedcesium carbonate (81.4 mg, 0.25 mmol) and methylamine (2 mol/L THFsolution, 0.125 ml, 0.25 mmol), and the mixture was stirred at roomtemperature for 5 hours. The reaction solution was filtered, and thefiltrate was fractionated and purified by LCMS to obtain compound 65F.

MS: m/z=358 [M+H]⁺.

Sixth Step

To a DMF (0.5 mL) solution of compound 65F was added a 2N aqueous sodiumhydroxide solution (0.2 mL), and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added ion-exchangeresin DOWEX (50W-X8), and the mixture was filtered, and washed with DMF.After concentration of the filtrate, trifluoroacetic acid (0.5 mL) wasadded, and the mixture was stirred at 80° C. for 4 hours. Afterconcentration of the reaction solution, water and chloroform were added,and the organic layer was separated. The organic layer was concentrated,and fractionation-purified by LCMS to obtain 6.47 mg of compound 65.

MS: m/z=254 [M+H]⁺.

According to Example 65, the following compounds were synthesized by thesame procedure.

TABLE 1 Example Structure MS Example 66

348 Example 67

296 Example 68

340 Example 69

348 Example 70

442 Example 71

318

TABLE 2 Example Structure MS Example 72

362 Example 73

388 Example 74

438 Example 75

298 Example 76

430 Example 77

442

TABLE 3 Example Structure MS Example 78

442 Example 79

454 Example 80

438 Example 81

492 Example 82

443

TABLE 4 Example Structure MS Example 83

513 Example 84

500 Example 85

454 Example 86

452 Example 87

480

TABLE 5 Example Structure MS Example 88

406 Example 89

445 Example 90

500 Example 91

416 Example 92

450

According to Example 65, compound 93 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 3.34 (3H, s), 3.57-3.68 (2H, m), 3.73 (2H, br s), 4.18(2H, s), 4.75 (2H, br s), 7.06-7.12 (2H, m), 7.21-7.24 (2H, m), 8.10(1H, s), 11.96 (1H, br s), 14.52 (1H, brs).

Example 94

First Step

Using compound 94A (WO 2007/049675), and according to the same procedureas that of the fifth step of Example 65, compound 94B was synthesized.

¹H-NMR (CDCl₃) δ: 3.00-3.09 (1H, m), 3.18 (3H, s), 3.44 (2H, dd, J=7.55,2.82 Hz), 4.02-4.08 (1H, m), 4.44-4.59 (3H, m), 4.86 (1H, d, J=13.57Hz), 5.25 (1H, s), 5.36 (2H, dd, J=14.87, 9.99 Hz), 6.74-6.84 (2H, m),7.09-7.60 (16H, m), 7.90 (1H, s), 10.07 (1H, t, J=5.87 Hz).

Second Step

To a MeCN (20 ml) solution of compound 94B (1.1 g, 1.655 mmol) wereadded DMAP (202 mg, 1.655 mmol) and Boc₂O (20 ml, 86 mmol) at roomtemperature under nitrogen stream, and the mixture was heated to refluxfor 5 hours. Further, Boc₂O (20 ml, 86 mmol) was added, and the mixturewas heated to reflux for 5 hours. After concentration under reducedpressure, to the residue were added ethanol (20.00 ml) and an aqueoussodium hydroxide solution (40%, 25 ml), and the mixture was stirred atroom temperature for 5 hours. To the reaction mixture were added ethylacetate-water to make the aqueous layer acidic. After extraction withethyl acetate (2×200 mL), the organic layer was washed with an aqueoussaturated sodium chloride solution. After drying with magnesium sulfate,the solvent was distilled off under reduced pressure. The crude productwas purified by silica gel column chromatography (CHCl₃/MeOH 20:1) toobtain compound 94C. (750 mg, 63%)

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.25-3.34 (3H, m), 3.79 (1H, d,J=13.73 Hz), 4.42 (1H, d, J=14.03 Hz), 5.11-5.27 (3H, m), 5.48 (1H, s),7.18-7.21 (5H, m), 7.33-7.49 (6H, m), 7.56-7.58 (2H, m), 7.74 (2H, d,J=7.32 Hz), 8.01 (1H, s).

Third Step

Using compound 94C, and according to the same procedure as that of thetenth step of Example 12, compound 94 was synthesized.

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.41-3.56 (4H, m), 4.50 (1H, d,J=13.57 Hz), 5.21 (1H, d, J=13.42 Hz), 5.58 (1H, s), 7.16-7.50 (8H, m),7.72 (2H, d, J=7.32 Hz), 7.93 (1H, s), 12.12 (1H, s).

Example 95

First Step

Compound 95A (WO 2006/116764, 1 g, 4.06 mmol) was dissolved in 28%aqueous ammonia, and the solution was stirred at room temperature for 12hours. After concentration of the reaction solution, the resultingresidue was neutralized with 2N hydrochloric acid, and the precipitatedsolid was suspended in ethyl acetate, filtered, and dried to obtain 1.14g (yield 100%) of compound 95B.

¹H-NMR (DMSO-d₆) δ: 5.14 (2H, s), 7.31 (1H, d, J=6.6 Hz), 7.34-7.41 (3H,m), 7.45-7.51 (2H, m), 8.17 (1H, d, J=6.6 Hz).

Second Step

To a DMF (10 ml) solution of compound 95B (3.00 g, 10.65 mmol) wereadded WSC HCl (3.06 g, 15.98 mmol) and HOBt (1.58 g, 11.7 mmol) at roomtemperature, the mixture was stirred for 10 minutes, and a methylamine33 wt % ethanol solution (1.50 g, 15.98 mmol) was added dropwise. Afterthe reaction solution was stirred at the same temperature for 2 hours,water was added, and the mixture was extracted with chloroform fivetimes. The extract was dried with sodium sulfate, the solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. From a fraction eluted with ethyl acetate-MeOH (6:4,v/v), 2.62 g (yield 95%) of compound 95C was obtained as a solid.

¹H-NMR (CDCl₃) δ: 2.77 (3H, d, J=4.8 Hz), 5.49 (2H, s), 6.57 (1H, d,J=6.9 Hz), 7.25-7.43 (5H, m), 7.48 (1H, t, J=6.0 Hz), 8.23 (1H, brs),9.77 (1H, brs).

Third Step

Into a DMF (10 ml) solution of compound 95C (2.62 g, 10.14 mmol) wassuspended potassium carbonate (4.20 g, 30.42 mmol) at room temperature,the suspension was stirred for 5 minutes,O-(2,4-dinitrophenyl)hydroxylamine (3.03 g, 15.21 mmol) was added, andthe mixture was stirred at the same temperature for 3 hours. To thereaction solution was added water, the mixture was extracted withchloroform five times, and the extract was dried with sodium sulfate.After the solvent was distilled off, the resulting oil was purified bysilica gel chromatography. From a fraction eluted with ethylacetate-MeOH (6:4, v/v), 1.41 g (yield 51%) of compound 95D was obtainedas a solid.

¹H-NMR (CDCl₃) δ: 2.62 (3H, d, J=5.1 Hz), 5.06 (2H, s), 5.22 (2H, s),6.18 (1H, d, J=7.8 Hz), 7.25-7.36 (5H, m), 5.89 (1H, d, J=7.8 Hz), 7.57(1H, q, J=5.1 Hz).

Fourth Step

A toluene (10 ml) solution of compound 95D (1.0 g, 3.66 mmol) were addedparaformaldehyde (109.9 mg, 3.66 mmol) and acetic acid (22 mg, 0.37mmol), and the mixture was heated to stir at 100° C. for 40 minutes.After cooling, the solvent was distilled off, the residue was dissolvedin DMF (10 ml) without purification, cesium carbonate (3.58 g, 10.98mmol) was added under ice-cooling, and the mixture was stirred for 10minutes. To the reaction solution was added benzohydryl bromide (1.36 g,5.49 mmol), the mixture was stirred at room temperature for 3 hours,water was added, and the mixture was extracted with ethyl acetate threetimes. The extract was washed with water three times, and dried withsodium sulfate. The solvent was distilled off, and the resulting oil waspurified by silica gel chromatography. From a fraction eluted with ethylacetate-MeOH (9:1, v/v), 1.26 g (yield 71%) of compound 95E was obtainedas a solid.

¹H-NMR (CDCl₃) δ: 2.91 (3H, s), 4.26 (1H, d, J=13.2 Hz), 4.77 (1H, d,J=13.2 Hz), 5.12 (1H, s), 5.42 (1H, J=13.2 Hz), 5.45 (1H, d, J=13.2 Hz),5.82 (1H, J=7.5 Hz), 6.71 (1H, d, J=7.5 Hz), 7.10-7.23 (5H, m),7.27-7.46 (6H, m), 7.52 (2H, d, J=6.9 Hz), 7.60-7.64 (2H, m).

Fifth Step

Compound 95E (100 mg, 0.221 mmol) was dissolved in trifluoroacetic acid(2 ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 50 mg (yield 63%) of compound 95.

¹H-NMR (CDCl₃) δ: 2.95 (3H, s), 4.36 (1H, d, J=13.2 Hz), 4.95 (1H, d,J=13.2 Hz), 5.22 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8Hz), 7.21 (5H, br s), 7.33-7.47 (4H, m), 7.55 (2H, d, J=6.6 Hz).

According to Example 95, the following compounds were synthesized by thesame procedure.

Example 96

¹H-NMR (CDCl₃) δ: 3.12-3.18 (1H, m), 3.21 (3H, s), 3.38-3.52 (2H, m),3.81 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.1 Hz), 4.52 (1H, d, J=13.2 Hz), 5.00(1H, d, J=13.2 Hz), 5.28 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.74 (1H, d,J=7.8 Hz), 7.14-7.21 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.5 Hz).

Example 97

¹H-NMR (CDCl₃) δ: 2.99-3.06 (0.54H, m), 3.18-3.23 (3.9H, m), 3.42-3.54(2.5H, m), 3.86-3.91 (0.42H, m), 4.03-4.08 (0.58H, m), 4.37 (0.58H, d,J=13.5 Hz), 4.54 (0.42H, d, J=13.8 Hz), 4.98 (0.58H, d, J=13.5 Hz), 5.08(0.42H, d, J=13.8 Hz), 5.36 (0.58H, s), 5.43 (0.42H, s), 5.70-5.77 (1H,m), 6.77 (0.42H, d, J=7.5 Hz), 6.94 (0.58H, d, J=7.8 Hz), 7.08-7.53 (6H,m), 7.60-7.78 (2H, m), 8.55 (0.58H, d, J=4.2 Hz), 8.72 (0.42H, d, J=3.9Hz).

Example 98

¹H-NMR (CDCl₃) δ: 0.930 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=6.9 Hz), 4.58(1H, d, J=12.6 Hz), 4.79 (1H, d, J=12.6 Hz), 4.83-4.90 (1H, m), 5.20(1H, s), 5.67 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.5 Hz), 7.07-7.09 (2H,m), 7.13-7.19 (3H, m), 7.34-7.46 (3H, m), 7.52 (1H, d, J=7.5 Hz).

Example 99

¹H-NMR (CDCl₃) δ: 3.30 (3H, s), 3.49 (1H, brs), 3.54-3.56 (2H, m), 3.73(1H, brs), 4.11 (2H, brs), 4.25 (1H, brs), 4.78 (1H, brs), 6.00 (1H, d,J=7.5 Hz), 8.33 (1H, d, J=7.5 Hz), 7.19-7.24 (3H, m), 7.34-7.37 (2H, m),7.38-7.48 (4H, m).

Example 100

¹H-NMR (CDCl₃) δ: 4.32 (1H, d, J=14.7 Hz), 4.41 (1H, d, J=12.9 Hz), 4.69(1H, d, J=14.7 Hz), 4.88 (1H, d, J=12.9 Hz), 4.97 (1H, s), 5.68 (1H, d,J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.91-6.98 (2H, m), 7.05-7.08 (2H, m),7.12-7.20 (7H, m), 7.30-7.32 (4H, m).

Example 101

¹H-NMR (CDCl₃) δ: 3.35 (3H, s), 3.66-3.69 (3H, m), 3.89 (1H, brs), 4.51(1H, brs), 4.64 (2H, brs), 5.05 (1H, brs), 5.89 (1H, d, J=7.5 Hz), 6.58(1H, d, J=7.5H), 7.11 (1H, d, J=7.2 Hz), 7.26-7.40 (1H, m), 7.54-7.62(2H, m), 7.86-7.93 (2H, m), 8.13 (1H, d, J=8.4 Hz).

¹H-NMR (CDCl₃) δ: 4.54 (1H, d, J=12.9 Hz), 4.56 (2H, s), 4.94 (1H, d,J=12.9 Hz), 5.14 (1H, s), 5.68 (1H, d, J=7.8 Hz), 6.20 (1H, d, J=3.0Hz), 6.25-6.27 (1H, m), 6.72 (1H, d, J=7.8 Hz), 7.10-7.37 (11H, m).

Example 103

¹H-NMR (CDCl₃) δ: 3.33 (3H, s), 3.63-3.66 (2H, m), 3.75 (2H, brs), 4.27(2H, brs), 4.67 (1H, brs), 5.00 (1H, brs), 6.09 (1H, d, J=7.8 Hz), 6.99(1H, d, J=7.8 Hz), 7.18 (1H, d, J=7.8 Hz), 7.27-7.32 (1H, m), 7.66-7.71(1H, m), 8.63-8.65 (1H, m).

Example 104

¹H-NMR (CDCl₃) δ: 3.12-3.22 (1H, m), 3.21 (3H, m), 3.38-3.55 (3H, m),3.74-3.80 (0.55H, m), 3.87-3.94 (0.44H, m), 4.46-4.54 (1H, m), 5.00-5.07(1H, m), 5.30-5.39 (1H, m), 5.70 (0.55H, d, J=7.5 Hz), 5.77 (0.45H, d,J=7.5 Hz), 6.74 (0.55H, d, J=7.8 Hz), 6.81 (0.45H, d, J=7.8 Hz),7.11-7.54 (7.45H, m), 7.90 (0.55H, d, J=7.8 Hz), 8.459-8.783 (2H, m).

Example 105

¹H-NMR (CDCl₃) δ: 3.34 (3H, s), 3.65-3.70 (4H, m), 4.18 (1H, brs), 4.21(1H, brs), 4.48 (1H, brs), 4.98 (1H, brs), 6.12 (1H, d, J=7.8 Hz), 6.97(1H, d, J=7.8 Hz), 7.36 (1H, d, J=7.5 Hz), 7.49 (1H, t, J=7.8 Hz),7.61-7.66 (2H, m).

Example 106

¹H-NMR (CDCl₃) δ: 2.54 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7, 5 Hz), 4.38(2H, brs), 4.77 (2H, brs), 6.27 (1H, d, J=7.5 Hz), 6.96-7.00 (2H, m),7.04-7.09 (3H, m), 7.19-7.33 (5H, m).

Example 107

First Step

To a DMF (30 ml) solution of compound 107A (3.0 g, 9.96 mmol)synthesized according to the method of synthesizing compound 95D wereadded paraformaldehyde (299 mg, 9.96 mmol) and acetic acid (1 ml), andthe mixture was heated to stir at 120° C. for 4 hours. After the solventwas distilled off, to the residue were added ethyl acetate-diisopropylether, and the precipitated solid was filtered to obtain 2.85 g (yield91%) of compound 107B.

¹H-NMR (CDCl₃) δ: 1.19 (6H, J=6.6 Hz), 4.34 (2H, J=7.5 Hz), 4.72-4.86(1H, m), 5.30 (2H, s), 5.49 (1H, t, J=7.5 Hz), 6.36 (1H, d, J=7.8 Hz),7.26-7.35 (4H, m), 7.37 (1H, d, J=7.8 Hz), 7.55-7.58 (2H, m).

Second Step

To an acetic acid (2 ml) solution of compound 107B (100 mg, 0.319 mmol)were added 96% sulfuric acid (0.5 ml) and bis(3-chlorophenyl)methanol(242.3 mg, 0.957 mmol) at room temperature, and the mixture was stirredat 80° C. for 2 hours. After the reaction solution was cooled to roomtemperature, water was added, and the mixture was extracted with ethylacetate three times. The organic layer was washed with water once, anddried with sodium sulfate. After the solvent was distilled off, to theresidue was added diisopropyl ether, and the precipitated solid wasfiltered to obtain 42 mg (yield 29%) of compound 107.

¹H-NMR (CDCl₃) δ: 0.953 (3H, d, J=3.9 Hz), 1.12 (3H, d, J=4.2 Hz), 4.51(1H, 13.5 Hz), 4.83 (1H, d, J=13.5 Hz), 4.83-4.92 (1H, m), 5.18 (1H, s),5.74 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 6.90 (1H, d, J=7.5 Hz),7.12 (2H, dd, J=7.2 Hz, 8.1 Hz), 7.19-7.22 (1H, m), 7.37-7.41 (3H, m),7.55 (1H, s).

According to Example 107, the following compounds were synthesized bythe same procedure.

Example 108

¹H-NMR (CDCl₃) δ: 0.465-0.549 (1H, m), 0.642-0.738 (1H, m), 0.754-0.907(2H, m), 2.71-2.79 (1H, m), 2.86 (1H, ddd, J=4.8 Hz, 5.7 Hz, 14.7 Hz),3.01 (2H, ddd, J=4.2 Hz, 16.0 Hz, 16.8 Hz), 3.88 (1H, ddd, J=4.8 Hz, 5.1Hz, 16.8 Hz), 4.08-4.14 (1H, m), 4.16 (1H, d, J=12.9 Hz), 4.70 (1H, d,J=12.9 Hz), 4.96 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.58 (1H, d, J=7.8Hz), 6.61 (1H, d, J=7.5 Hz), 6.92 (1H, dd, J=6.0 Hz, 7.5 Hz), 7.11-7.80(6H, m).

Example 109

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 1.18 (3H, d, J=6.9 Hz), 2.82(1H, ddd, J=4.5 Hz, 4.8 Hz, 14.1 Hz), 3.08 (1H, ddd, J=4.2 Hz, 13.2 Hz,17.7 Hz), 3.53 (1H, ddd, J=4.2 Hz, 4.5 Hz, 17.7 Hz), 4.27 (1H, d, J=12.9Hz), 4.26-4.37 (1H, m), 4.62-4.71 (1H, m), 4.68 (1H, d, J=12.9 Hz), 5.05(1H, s), 5.71 (1H, d, J=7.5 Hz), 6.63 (2H, d, J=7.2 Hz), 6.90 (1H, t,J=7.5 Hz), 7.08-7.63 (6H, m).

Example 110

¹H-NMR (CDCl₃) δ: 3.16-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m),3.86 (1H, ddd, J=3.6 Hz, 3.6 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01(1H, d, J=13.2 Hz), 5.30 (1H, s), 5.76 (1H, d, J=7.5 Hz), 6.72 (1H, d,J=7.5 Hz), 6.90 (2H, t, J=8.4 Hz), 7.06-7.18 (4H, m), 7.51 (2H, dd,J=5.4 Hz, 8.7 Hz).

Example 111

¹H-NMR (CDCl₃) δ: 0.903 (1.3H, d, J=6.9 Hz), 0.982 (1.5H, d, J=6.6 Hz),1.08-1.14 (3.2H, m), 4.55 (1H, dd, J=13.2 Hz, 16.5 Hz), 4.78-4.93 (2H,m), 5, 20 (1H, s), 5.66 (0.58H, d, J=7.5 Hz), 5.75 (0.42H, d, J=7.5 Hz),6.67 (0.55H, d, J=7.5 Hz), 6.73 (0.45H, d, J=7.5 Hz), 6.92 (0.45H, d,J=7.2 Hz), 7.04-7.59 (8.6H, m).

Example 112

¹H-NMR (CDCl₃) δ: 3.22 (3H, s), 3.24-3.32 (1H, m), 3.47-3.50 (2H, m),3.84 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz), 4.51 (1H, d, J=13.5 Hz), 5.03(1H, d, J=13.5 Hz), 5.32 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.80 (1H, d,J=7.8 Hz), 6.84 (1H, d, J=7.8 Hz), 6.93 (2H, t, J=8.4 Hz), 7.06-7.20(2H, m), 7.25-7.29 (2H, m), 7.39-7.47 (1H, m).

Example 113

¹H-NMR (CDCl₃) δ: 0.88 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.6 Hz), 2.10(3H, s), 4.62-4.69 (1H, m), 4.79-4.92 (2H, m), 5.32 (1H, s), 5.64(0.74H, 7.5 Hz), 5.72 (0.26H, d, J=7.5 Hz), 6.61 (0.74H, d, J=7.8 Hz),6.82 (0.26H, d, J=7.8 Hz), 6.96-7.52 (8.26H, m), 7.48 (0.74H, d, J=7.5Hz).

Example 114

¹H-NMR (CDCl₃) δ: 0.976 (2H, d, J=6.9 Hz), 1.09-1.14 (3H, m), 5.63(0.74H, d, J=7.8 Hz), 5.65 (0.74H, s), 5.73 (0.26H, d, J=7.8 Hz), 6.20(0.26H, s), 6.65 (0.74H, d, J=7.8 Hz), 6.79 (0.26H, d, J=7.8 Hz),7.05-7.24 (4.26H, m), 7.31-7.56 (4H, m), 8.02 (0.74H, d, J=6.3 Hz).

Example 115

¹H-NMR (CDCl₃) δ: 0.893 (1.2H, d, J=6.6 Hz), 0.958 (1.8H, d, J=6.9 Hz),1.09-1.13 (3H, m), 4.44 (0.56H, d, J=13.2 Hz), 4.63 (0.44H, d, J=13.5Hz), 4.81-4.93 (2H, m), 5.35 (1H, m), 5.67 (0.56H, d, J=7.8 Hz), 5.72(0.44H, d, J=7.8 Hz), 6.67-6.73 (1H, m), 7.03 (1H, d, J=6.6 Hz),7.20-7.51 (5H, m), 7.75 (1H, d, 0.8.4 Hz), 8.06 (0.88H, d, J=8.7 Hz),8.33 (1.1H, d, J=8.7 Hz).

Example 116

¹H-NMR (CDCl₃) δ: 0.91-0.0.948 (3H, m), 1.10-1.14 (3H, m), 3.61-3.68(1H, m), 4.44 (0.56H, d, J=12.9 Hz), 4.59 (0.44H, d, J=12.9 Hz),4.79-4.91 (2H, m), 5.29 (1H, s), 5.67-5.69 (1H, m), 6.63-6.70 (2H, m),6.90-7.81 (8H, m).

Example 117

¹H-NMR (CDCl₃) δ: 3.19-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m),3.85 (1H, ddd, J=3 Hz, 4.2 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01(1H, d, J=13.2 Hz), 5.28 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.73 (1H, d,J-=7.8 Hz), 7.04 (2H, d, J=8.4 Hz), 7.19 (2H, d, 8.4 Hz), 7.36-7.50 (4H,m).

Example 118

¹H-NMR (CDCl₃) δ: 0.914-0.957 (3H, m), 1.08-1.14 (3H, m), 2.20 (1.4H,s), 2.39 (1.6H, s), 4.56 (0.48H, d, J=4.5 Hz), 4.60 (0.52H, d, J=4.2Hz), 4.77-4.89 (2H, m), 5.16 (1H, s), 5.66-5.70 (1H, m), 6.65-6.69 (1H,m), 6.85-6.91 (1H, m), 6.98-7.10 (2H, m), 7.14-7.19 (2H, m), 7.30-7.39(2H, m), 7.44 (1H, t, J=6.9 Hz), 7.51 (1H, d, J=6.9 Hz).

Example 119

¹H-NMR (CDCl₃) δ: 0.893-0.982 (3H, m), 1.08-1.14 (3H, m), 4.49-4.60 (1H,m), 4.78-4.90 (2H, m), 5.20 (1H, s), 5.65 (0.57H, J=7.5 Hz), 5.76(0.43H, d, J=7.8 Hz), 6.64-6.70 (1H, m), 7.03 (2H, d, J=8.1 Hz),7.10-7.20 (3H, m), 7.28-7.51 (4H, m).

Example 120

¹H-NMR (CDCl₃) δ: 0.526 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.6 Hz), 4.69(1H, d, J=13.8 Hz), 4.75-4, 83 (1H, m), 4.86 (1H, d, J=13.8 Hz), 5.69(1H, d, J=7.8 Hz), 6.03 (1H, s), 0.6.70 (1H, d, J=7.8 Hz), 7.16 (5H, s),7.40-7.48 (2H, m), 7.67 (1H, t, J=7.8 Hz), 7.81-7.91 (3H, m), 8.16 (1H,d, J=7.2 Hz).

Example 121

¹H-NMR (CDCl₃) δ: 0.947 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=7.2 Hz), 2.22(3H, s), 2.37 (3H, s), 4.58 (1H, d, J=12.9 Ha), 4.76 (1H, d, J=12.9 Hz),4.78-4.88 (1H, m), 5.13 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.67 (1H, d,J=7.8 Hz), 6.72 (1H, s), 6.90-6.98 (4H, m), 7.22 (2H, d, J=7.8 Hz), 7.38(2H, d, J=7.8 Hz).

Example 122

¹H-NMR (CDCl₃) δ: 0.932 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=6.9 Hz), 4.44(1H, d, J=13.2 Hz), 4.86 (1H, d, J=13.2 Hz), 4.87-4.93 (1H, m), 5.38(1H, s), 5.67 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 7.21-7.24 (1H,m), 7.32-7.40 (2H, m), 7.52 (1H, d, J=7.5 Hz), 7.60-7.72 (2H, m),7.77-7.79 (2H, m).

Example 123

¹H-NMR (CDCl₃) δ: 3.08-3.17 (1H, m), 3.23 (3H, s), 3.40-3.54 (2H, m),3.71 (3H, s), 3.82 (3H, s), 3.95 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz),4.48 (1H, d, J=13.5 Hz), 4.96 (1H, d, J=13.5 Hz), 5.16 (1H, s), 5.76(1H, d, J=7.5 Hz), 6.70 (2H, d, J=9.0 Hz), 6.73 (1H, d, J=7.5 Hz), 6.94(2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz).

Example 124

¹H-NMR (CDCl₃) δ: 0.966 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.9 Hz), 3.67(3H, s), 3.83 (3H, s), 4.60 (1H, d, J=12.9 Hz), 4.78 (1H, d, J=12.9 Hz),4.80-4.90 (1H, m), 5.13 (1H, m), 5.23 (1H, d, J=7.8 Hz), 6.66 (2H, d,J=7.2 Hz), 6.72-6.87 (2H, m), 6.87-6.90 (1H, m), 7.06-7.11 (3H, m), 7.34(1H, t, J=8.1 Hz).

Example 125

¹H-NMR (DMSO-d₆) δ: 1.05 (2H, d, J=7.0 Hz), 1.15 (1H, d, J=7.5 Hz),2.73-3.63 (8H, m), 4.20-4.93 (4H, m), 5.25 (0.4H, s), 5.30 (0.6H, s),5.46 (1H, d, J=7.8 Hz), 6.68-7.46 (11H, m).

MS: m/z=446 [M+H]⁺.

Example 126

First Step

Compound 95B (1.00 g, 3.55 mmol) and cyclopropanamine (0.492 ml, 7.10mmol) were added to pyridine (20 ml), 1-hydroxybenzotriazole (544 mg,3.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.36 g, 7.10 mmol) were sequentially added, and themixture was stirred at room temperature for 18 hours. After the solventwas distilled off under reduced pressure, the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,95:5, v/v) and, subsequently, amino column chromatography(chloroform-methanol, 99:1, v/v) to obtain 1.19 g of compound 126A as acolorless solid.

¹H-NMR (CDCl₃) δ: 0.22 (1H, m), 0.70 (2H, m), 2.76-2.83 (1H, m), 5.50(2H, s), 6.59 (1H, dd, J=7.0, 1.9 Hz), 7.44 (5H, d, J=0.7 Hz), 7.53 (1H,dd, J=6.9, 6.2 Hz), 8.30 (1H, brs), 9.71 (1H, brs).

Second Step

Compound 126A (1.19 g, 4.19 mmol) was dissolved in DMF (15 ml),potassium carbonate (2.90 g, 20.1 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (1.67 g, 8.38 mmol) was added, andthe mixture was stirred at room temperature for 18 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97:3→95:5, v/v) toobtain 851 mg of compound 126B as a yellow solid.

¹H-NMR (CDCl₃) δ: 0.41-0.46 (2H, m), 0.76 (2H, m), 2.73-2.81 (1H, m),5.19 (2H, s), 5.61 (2H, s), 6.26 (1H, d, J=7.2 Hz), 7.38 (5H, s), 7.44(1H, d, J=7.8 Hz), 7.70 (1H, s).

Third Step

Compound 126B (847 mg, 2.83 mmol) and paraformaldehyde (255 mg, 8.49mmol) were added to ethanol (12 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95:5→90:10, v/v) and, subsequently, amino column chromatography(chloroform-methanol, 97:3, v/v), methylene chloride-ethyl ether wereadded, and the precipitated solid was filtered to obtain 665 mg ofcompound 126C as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.61-0.66 (2H, m), 0.87 (2H, m), 2.68-2.76 (1H, m),4.32 (2H, d, J=7.9 Hz), 5.28 (2H, s), 6.33 (1H, d, J=7.7 Hz), 6.45 (1H,t, J=7.7 Hz), 7.33 (3H, m), 7.38 (1H, d, J=7.7 Hz), 7.52 (2H, m).

Fourth Step

Compound 126C (100 mg, 0.321 mmol) was dissolved in DMF (0.5 ml), cesiumcarbonate (314 mg, 0.964 mmol) and (bromomethylene)dibenzene (119 mg,0.482 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,97:3→95:5, v/v) to obtain 124 mg of compound 126D as a colorless gummysubstance.

¹H-NMR (CDCl₃) δ: 0.37-0.47 (2H, m), 0.74 (2H, m), 2.63-2.68 (1H, m),4.35 (1H, d, J=13.4 Hz), 4.65 (1H, d, J=13.4 Hz), 5.07 (1H, s), 5.40(1H, d, J=10.7 Hz), 5.47 (1H, d, J=10.5 Hz), 5.79 (1H, d, J=7.6 Hz),6.67 (1H, d, J=7.8 Hz), 7.04-7.62 (15H, m).

Fifth Step

To compound 126D obtained in the fourth step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1.5hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and 2N hydrochloric acid, and the mixturewas extracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, methylenechloride-ethyl ether were added, and the precipitated solid was filteredto obtain 52 mg of compound 126 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: −0.19-0.06 (1H, m), 0.44-0.54 (1H, m), 0.82 (2H, m),2.62-2.69 (1H, m), 4.21 (1H, d, J=13.3 Hz), 5.11 (1H, d, J=13.1 Hz),5.32 (1H, s), 5.47 (1H, t, J=11.1 Hz), 7.13 (1H, d, J=7.6 Hz), 7.23 (3H,m), 7.28-7.47 (8H, m), 7.69 (2H, t, J=8.5 Hz).

MS: m/z=388 [M+H]⁺.

Example 127

According to Example 126, compound 127 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 0.86 (1.5H, d, J=7.0 Hz), 1.04 (1.5H, d, J=7.2 Hz),3.08 (1.5H, s), 3.16 (1.5H, s), 4.52-5.05 (3H, m), 5.48 (2H, m),7.31-7.47 (9H, m), 7.66 (2H, t, J=8.4 Hz).

MS: m/z=420 [M+H]⁺.

Example 128

First Step

Compound 95B (2.40 g, 8.52 mmol) and ethyl 3-aminopropanoatehydrochloride (2.62 g, 17.0 mmol) were added to pyridine (30 ml),1-hydroxybenzotriazole (1.31 g, 8.52 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.27 g,17.0 mmol) were sequentially added, and the mixture was stirred at roomtemperature for 2 hours. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by amino columnchromatography (chloroform-methanol, 95:5, v/v) to obtain 1.90 g ofcompound 128A as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 2.48 (2H, t, J=6.4 Hz), 3.58(2H, q, J=6.3 Hz), 4.17 (2H, q, J=7.1 Hz), 5.59 (2H, s), 6.57 (1H, dd,J=7.1, 1.6 Hz), 7.37-7.52 (6H, m), 8.73 (1H, brs), 9.72 (1H, brs).

Second Step

Compound 128A (2.58 g, 7.49 mmol) was dissolved in DMF (30 ml),potassium carbonate (5.18 g, 37.5 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (2.98 g, 15.0 mmol) was added, andthe mixture was stirred at room temperature for 20 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97:3→95:5, v/v) and,subsequently, silica gel column chromatography (chloroform-methanol,95:5→92:8, v/v) to obtain 1.67 g of compound 128B as a yellow solid.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.2 Hz), 2.42 (2H, t, J=6.6 Hz), 3.43(2H, q, J=6.4 Hz), 4.12 (2H, q, J=7.1 Hz), 5.13 (2H, s), 5.53 (2H, s),6.21 (1H, d, J=7.6 Hz), 7.33 (5H, s), 7.39 (1H, d, J=7.6 Hz), 7.85 (1H,t, J=5.6 Hz).

Third Step

Compound 128B (1.66 g, 4.62 mmol) and paraformaldehyde (416 mg, 13.9mmol) were added to ethanol (20 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1→95:5,v/v) to obtain 1.57 g of compound 128C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.2 Hz), 2.70 (2H, t, J=5.7 Hz), 3.57(2H, t, J=5.8 Hz), 4.13 (2H, q, J=7.1 Hz), 4.50 (2H, d, J=7.9 Hz), 5.27(2H, s), 5.87 (1H, t, J=7.8 Hz), 6.32 (1H, d, J=7.6 Hz), 7.31 (4H, m),7.54 (2H, m).

Fourth Step

Compound 128C (1.00 g, 2.69 mmol) was dissolved in DMF (10 ml), cesiumcarbonate (2.63 g, 8.08 mmol) and (bromomethylene)dibenzene (998 mg,4.04 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform/methanol,98:2, v/v) to obtain 500 mg of compound 128D as a colorless gummysubstance.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.3 Hz), 2.46 (1H, m), 2.70-2.80 (1H,m), 2.87-2.96 (1H, m), 4.11 (2H, q, J=7.3 Hz), 4.12 (1H, m), 4.48 (1H,d, J=13.7 Hz), 4.85 (1H, d, J=13.7 Hz), 5.10 (1H, s), 5.47 (2H, s), 5.83(1H, d, J=8.0 Hz), 6.73 (1H, d, J=8.0 Hz), 7.37 (15H, m).

Fifth Step

To compound 128D (40 mg, 0.074 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, methylenechloride-ethyl ether were added, and the precipitated solid was filteredto obtain 20 mg of compound 128 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, t, J=7.1 Hz), 2.45-2.58 (3H, m), 3.70 (1H,m), 4.02 (2H, q, J=7.1 Hz), 4.39 (1H, d, J=13.4 Hz), 5.09 (1H, d, J=13.3Hz), 5.48 (1H, d, J=3.2 Hz), 5.51 (1H, s), 7.19-7.38 (7H, m), 7.45 (2H,t, J=7.3 Hz), 7.69 (2H, d, J=7.2 Hz).

MS: m/z=448 [M+H]⁺.

Example 129

First Step

Compound 128D (426 mg, 0.792 mmol) was dissolved in ethanol (3 ml) andTHF (3 ml), a 2N aqueous sodium hydroxide solution (1.19 ml, 2.38 mmol)was added, and the mixture was stirred at room temperature for 1.5hours. To the reaction solution was added 2N hydrochloric acid, and themixture was extracted with chloroform, and dried with sodium sulfate. Tothe resulting crude product were added methylene chloride-ethyl ether,and the precipitated solid was filtered to obtain 359 mg of compound129A as a colorless solid.

Second Step

To compound 129A (40 mg, 0.079 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 3 with sodiumbicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 25 mg of compound 129 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.31-2.41 (1H, m), 2.57 (1H, m), 3.63-3.72 (1H, m),4.37 (1H, d, J=13.3 Hz), 5.09 (1H, d, J=13.3 Hz), 5.47 (1H, s), 5.50(1H, d, J=7.8 Hz), 7.28 (7H, m), 7.44 (2H, t, J=7.5 Hz), 7.69 (2H, d,J=7.2 Hz), 12.40 (1H, brs).

MS: m/z=420 [M+H]⁺.

Examples 130

First Step

Compound 129A (50 mg, 0.098 mmol) was added to DMF (1 ml),1-hydroxybenzotriazole (14 mg, 0.098 mmol), dimethylamine hydrochloride(24 mg, 0.29 mmol), triethylamine (0.048 ml, 0.34 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15mmol) were added, and the mixture was stirred at room temperature for1.5 hours. The reaction solution was poured into water, and the mixturewas extracted with ethyl acetate, washed with sodium bicarbonate water,and dried with sodium sulfate. The solvent was distilled off underreduced pressure to obtain compound 130A as a colorless gummy substance.

Second Step

To compound 130A obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 2hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and an aqueous ammonium chloride solution,and the mixture was extracted with chloroform, and dried with sodiumsulfate. The solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 25 mg of compound 130 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.33-2.43 (1H, m), 2.66 (1H, m), 2.78 (3H, s), 2.89(3H, s), 3.56 (2H, m), 4.45 (1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz),5.47 (s, 1H), 5.49 (1H, d, J=7.5 Hz), 7.27 (7H, m), 7.44 (2H, t, J=7.3Hz), 7.69 (2H, d, J=7.3 Hz).

Example 131

According to Example 130, compound 131 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.60-2.77 (3H, m), 3.94 (1H, m), 4.42 (1H, d, J=13.4Hz), 5.15 (1H, d, J=13.4 Hz), 5.49 (1H, s), 5.55 (1H, d, J=7.2 Hz), 7.07(1H, t, J=7.3 Hz), 7.12-7.49 (13H, m), 7.73 (2H, d, J=7.2 Hz), 10.01(1H, s).

MS: m/z=495 [M+H]⁺.

Example 132

According to Example 130, compound 132 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.14 (3H, s), 3.65 (4H, m), 4.34 (1H, d, J=13.6 Hz),5.06 (1H, d, J=13.6 Hz), 5.42 (1H, s), 5.53 (1H, d, J=7.5 Hz), 7.42-7.58(16H, m).

MS: m/z=509 [M+H]⁺.

Example 133

According to Example 130, compound 133 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.08-1.55 (8H, m), 2.33 (1H, m), 2.68 (1H, m), 4.45(1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 5.50 (2H, brs), 7.46-7.68(11H, m).

MS: m/z=487 [M+H]⁺.

Example 134

According to Example 130, compound 134 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.34-2.40 (1H, m), 2.61-2.77 (1H, m), 3.51-3.69(10H, m), 4.44 (1H, d, J=13.4 Hz), 5.03-5.11 (1H, d, J=13.4 Hz), 5.51(2H, s), 7.18-7.52 (9H, m), 7.69-7.75 (2H, m).

Example 135

First Step

Compound 95B (1.50 g, 5.32 mmol) and tert-butyl2-aminoethyl(methyl)carbamate (1.86 g, 10.7 mmol) were added to pyridine(20 ml), 1-hydroxybenzotriazole (815 mg, 5.32 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g,10.7 mmol) were sequentially added, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was poured into 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate, anddried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by amino columnchromatography (chloroform-methanol, 95:5, v/v) and, subsequently,silica gel column chromatography (chloroform-methanol, 95:5, v/v) toobtain 1.63 g of compound 135A as a colorless gummy substance.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.82 (3H, s), 3.28 (4H, m), 5.59 (2H,s), 6.57 (1H, d, J=6.0 Hz), 7.46 (6H, m), 8.46 (1H, m), 9.68 (1H, brs).

Second Step

Compound 135A (1.05 g, 2.62 mmol) was dissolved in DMF (15 ml),potassium carbonate (1.81 g, 13.1 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (1.04 g, 5.23 mmol) was added, andthe mixture was stirred at room temperature for 18 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97:3→95:5, v/v) toobtain 887 mg of compound 135B as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.84 (3H, s), 3.38 (4H, m), 5.33 (2H,s), 5.68 (1H, brs), 5.80 (1H, brs), 6.35 (1H, d, J=7.6 Hz), 6.74 (1H,brs), 7.39 (5H, brm), 7.52 (1H, t, J=9.5 Hz).

Third Step

Compound 135B (880 mg, 2.11 mmol) and paraformaldehyde (190 mg, 6.34mmol) were added to ethanol (18 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, and the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95:5→90:10 v/v) and, subsequently, amino column chromatography(chloroform-methanol, 97:3, v/v) to obtain 721 mg of compound 135C as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.29 (9H, s), 2.95 (3H, s), 4.38 (2H, brs), 5.33 (2H,brs), 6.36 (1H, d, J=7.6 Hz), 6.85 (1H, t, J=7.4 Hz), 7.33 (4H, m), 7.55(2H, m).

MS: m/z=429 [M+H]⁺.

Fourth Step

Compound 135C (720 mg, 1.68 mmol) was dissolved in DMF (3.5 ml), cesiumcarbonate (1.64 g, 5.04 mmol) and (bromomethylene)dibenzene (623 mg,2.52 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,97:3→95:5 v/v) to obtain 732 mg of compound 135D.

Fifth Step

To compound 135D (727 mg, 1.22 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml). After stirring at room temperature for 1 hour, thesolvent was distilled off under reduced pressure. Saturated sodiumbicarbonate water was added, the mixture was extracted with chloroform,and the extract was dried with sodium sulfate. The solvent was distilledoff under reduced pressure, to the resulting crude product were addedmethylene chloride-ethyl ether, and the precipitated solid was filteredto obtain 575 mg of compound 135E as a colorless solid.

Sixth Step

To compound 135E (50 mg, 0.10 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1.5 hours.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and an aqueous ammonium chloride solution, themixture was extracted with chloroform, and the extract was dried withsodium sulfate. After the solvent was distilled off under reducedpressure, ethylene chloride-ethyl ether were added, and the precipitatedsolid was filtered to obtain 15 mg of compound 135 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 2.80 (1H, s), 3.12 (3H, m), 3.87 (1H,m), 4.37 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.4 Hz), 5.52 (1H, s), 5.53(1H, d, J=5.5 Hz), 7.15-7.70 (11H, m).

MS: m/z=405 [M+H]⁺.

Example 136

First Step

Compound 135E (50 mg, 0.10 mmol) was dissolved in methylene chloride (1ml), triethylamine (0.042 ml, 0.30 mmol) and acetyl chloride (0.011 ml,0.15 mmol) were added, and the mixture was stirred at room temperaturefor 1 hour. The solvent was distilled off under reduced pressure, andthe resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 97:3→95:5, v/v) and, subsequently,amino column chromatography (chloroform-methanol, 97:3, v/v) to obtain72 mg of compound 136A as a colorless solid.

Second Step

To compound 136A obtained in the first step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1.5hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and an aqueous ammonium chloride solution,the mixture was extracted with chloroform, and the extract was driedwith sodium sulfate. After the solvent was distilled off under reducedpressure, methylene chloride-ethyl ether were added, and theprecipitated solid was filtered to obtain 23 mg of compound 136 as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 1.89 (2H, s), 1.92 (1H, s), 2.73 (1H, s), 2.95 (2H,s), 3.00-3.06 (1H, m), 3.43 (2H, m), 3.80 (1H, m), 4.34 (0.7H, d, J=13.3Hz), 4.45 (0.3H, d, J=13.1 Hz), 5.11 (1H, m), 5.49 (2H, m), 7.20-7.73(11H, m).

Example 137

According to Example 136, compound 137 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.95 (3H, s), 3.13-4.07 (4H, m), 4.46 (1H, d, J=13.2Hz), 5.16 (1H, d, J=13.0 Hz), 5.51 (1H, d, J=7.3 Hz), 5.62 (1H, s),7.17-7.78 (16H, m).

MS: m/z=509 [M+H]⁺.

Example 138

According to Example 136, compound 138 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.62 (3H, s), 3.03-3.22 (4H, m), 3.72 (2H, d, J=13.3Hz), 4.39 (1H, d, J=13.3 Hz), 5.08 (1H, d, J=13.3 Hz), 5.53 (1H, d,J=7.8 Hz), 5.55 (1H, s), 7.19-7.79 (16H, m).

MS: m/z=545 [M+H]⁺.

Example 139

According to Example 136, compound 139 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.72 (3H, s), 2.88 (3H, s), 3.12-3.24 (3H, m),3.75-3.80 (1H, m), 4.37 (1H, d, J=13.0 Hz), 5.10 (1H, d, J=13.4 Hz),5.51 (1H, d, J=7.6 Hz), 5.54 (1H, s), 7.19-7.46 (19H, m), 7.72 (2H, d,J=7.0 Hz).

MS: m/z=483 [M+H]⁺.

Example 140

According to Example 136, compound 140 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.88 (3H, s), 2.98-3.12 (3H, m), 3.77 (1H, m), 4.31(1H, d, J=13.3 Hz), 5.13 (1H, d, J=13.3 Hz), 5.51 (1H, s), 5.52 (1H, d,J=7.6 Hz), 7.13-7.46 (9H, m), 7.71 (2H, d, J=7.2 Hz).

MS: m/z=469 [M+H]⁺.

Example 141

According to Example 136, compound 141 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.07 (9H, s), 2.84 (1H, m), 3.19 (2H, d, J=3.9 Hz),3.96 (1H, d, m), 4.28 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=13.1 Hz), 5.52(1H, s), 5.56 (1H, t, J=4.2 Hz), 7.25-7.59 (10H, m), 7.75 (2H, d, J=7.7Hz).

MS: m/z=475 [M+H]⁺.

Example 142

According to Example 136, compound 142 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.10 (6H, m), 2.98 (3H, m), 3.78 (1H, m), 4.27 (1H,d, J=13.6 Hz), 4.68 (1H, m), 5.11 (1H, d, J=12.8 Hz), 5.51 (2H, m),7.07-7.46 (10H, m), 7.70 (2H, d, J=7.2 Hz).

MS: m/z=477 [M+H]⁺.

Example 143

According to Example 136, compound 143 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.89 (3H, m), 3.62 (1H, m), 4.17 (1H, d, J=13.1 Hz),4.99 (1H, d, J=13.1 Hz), 5.45 (1H, s), 5.51 (1H, d, J=7.8 Hz), 7.18-7.77(17H, m).

MS: m/z=531 [M+H]⁺.

Example 144

First Step

To compound 144A synthesized according to the first to fifth steps ofExample 135 were added formic acid and formalin, and the mixture wasstirred at 80 degree for 1.5 hours. The solvent was distilled off underreduced pressure, saturated sodium bicarbonate water was added, then themixture was extracted with chloroform, and the extract was dried withsodium sulfate. The solvent was concentrated under reduced pressure, andthe resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 95:5→92:8, v/v) to obtain 26 mg ofcompound 144B.

¹H-NMR (CDCl₃) δ: 2.06 (6H, s), 2.18-2.26 (1H, m), 2.36-2.45 (1H, m),2.89-2.98 (1H, m), 3.91 (1H, dt, J=14.1, 5.9 Hz), 4.43 (1H, d, J=13.6Hz), 4.82 (1H, d, J=13.4 Hz), 5.20 (1H, s), 5.41 (1H, d, J=10.8 Hz),5.46 (1H, d, J=10.7 Hz), 5.80 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.8 Hz),7.05-7.64 (15H, m).

Second Step

To compound 144B obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and an aqueous ammonium chloride solution, thenthe mixture was extracted with chloroform, and the extract was driedwith sodium sulfate. After the solvent was distilled off under reducedpressure, methylene chloride-ethyl ether were added, and theprecipitated solid was filtered to obtain 13 mg of compound 144 as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 2.17 (6H, s), 2.38-2.46 (3H, m), 3.59 (1H, m), 4.41(1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.3 Hz), 5.50 (1H, d, J=6.4 Hz),5.51 (1H, s), 7.19-7.47 (9H, m), 7.66 (2H, d, J=7.3 Hz).

MS: m/z=419 [M+H]⁺.

Example 145

First Step

To a dichloromethane (5 ml) solution of compound 95E (300 mg, 0.664mmol) was added NBS (130 mg, 0.731 mmol) under ice-cooling, temperaturewas raised to room temperature and, thereafter, the mixture was refluxedfor 1 hour. After the solvent was distilled off, the resulting residuewas purified by silica gel chromatography. The materials were elutedfirstly with n-hexane-ethyl acetate (1:1, v/v) and, then, with ethylacetate. Concentration of an objective fraction afforded 326.7 mg (yield93%) of compound 145A as a solid.

¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 4.27 (1H, d, J=13.5 Hz), 4.82 (1H, d,J=13.5 Hz), 5.13 (1H, s), 5.41 (2H, s), 5.41-7.12 (2H, m), 7.15 (1H, s),7.17-7.28 (3H, m), 7.31-7.47 (6H, m), 7.52 (2H, d, J=6.6 Hz), 7.63-7.67(2H, m).

Second Step

To a DMF (3 ml) solution of compound 145A (100 mg, 0.189 mmol) wereadded a solution of potassium carbonate (78.4 mg, 0.567 mmol) in water(0.5 ml), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane(47.6 mg, 0.284 mmol) and tetakistriphenylphosphinepalladium (21.8 mg,0.189 mmol), and the mixture was heated to stir at 80° C. for 4 hours.After the reaction solution was cooled to room temperature, water wasadded, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water three times, and dried with sodium sulfateand, thereafter, the resulting oil was purified by silica gelchromatography. Elution with only ethyl acetate, and concentration of anobjective fraction afforded 42.0 mg (yield 45%) of compound 145B as anoil.

¹H-NMR (CDCl₃) δ: 1.73 (3H, s), 2.92 (3H, s), 4.29 (1H, d, J=13.5 Hz),4.83 (1H, d, J=13.5 Hz), 4.96-4.97 (1H, m), 5.15 (1H, s), 5.21-5.21 (1H,m), 5.37 (1H, d, J=10.8 Hz), 5.40 (1H, d, J=10.8 Hz), 6.82 (1H, s),7.15-7.21 (5H, m), 7.27-7.47 (6H, m), 7.54 (2H, d, J=6.9 Hz), 7.64-7.69(2H, m).

Third Step

To a THF (2 ml) solution of compound 145B (40 mg, 0.081 mmol) was added10% Pd-C (8 mg), and the mixture was subjected to a catalytic reductionunder hydrogen stream. The catalyst was removed by filtration, and thefiltrate was concentrated. The resulting residue was washed with etherto obtain 6.8 mg (yield 21%) of compound 145.

¹H-NMR (CDCl₃) δ: 0.629 (3H, d, J=6.9 Hz), 0.900 (3H, d, J=6.9 Hz),2.87-3.00 (1H, m), 2.94 (3H, s), 4.37 (1H, d, J=13.2 Hz), 4.93 (1H, d,J=13.2 Hz), 5.21 (1H, s), 6.69 (1H, s), 7.21 (5H, s), 7.35-7.47 (3H, m),7.57 (2H, d, J=7.5 Hz).

Example 146

According to Example 145, compound 146 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 0.738 (3H, t, J=7.2 Hz), 1.05-1.18 (2H, m), 2.01-2.18(2H, m), 2.94 (3H, s), 4.35 (1H, d, J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz),5.22 (1H, s), 6.71 (1H, s), 7.20 (5H, s), 7.35-7.47 (3H, m), 7.55 (2H,d, J=6.9 Hz).

Example 147

First Step

Compound 145A (60 mg, 0.113 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 30 mg (yield 60%) of compound 147.

¹H-NMR (CDCl₃) δ: 2.97 (3H, s), 4.36 (1H, d, J=13.2 Hz), 5.01 (1H, d,J=13.2 Hz), 5.21 (1H, s), 7.14 (1H, s), 7.17-7.25 (5H, m), 7.36-7.48(3H, m), 7.54 (2H, d, J=7.2 Hz).

Example 148

Compound 145B (41 mg, 0.083 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 12 mg (yield 36%) of compound 148.

¹H-NMR (CDCl₃) δ: 1.70 (3H, s), 2.95 (3H, s), 4.36 (1H, d, J=12.9 Hz),4.95 (1H, d, J=12.9 Hz), 4.96-4.98 (1H, m), 5.23 (1H, s), 5.32-5.33 (1H,m), 6.86 (1H, s), 7.21 (5H, s), 7.35-7.48 (3H, m), 7.56 (2H, d, J=7.2Hz).

Example 149

To a THF (2 ml) solution of compound 145A (100 mg, 0.189 mg) were addeda 2N methylzinc chloride THF solution (0.377 ml, 0.754 mmol) andtetrakistriphenylphosphinepalladium (10.9 mg, 0.0945 mmol) at roomtemperature, and the mixture was heated to stir at 60° C. for 4 hours.After the reaction solution was cooled to room temperature, water wasadded, and the mixture was extracted with chloroform three times. Afterthe extract was dried with sodium sulfate, the solvent was distilledoff, and the resulting oil was purified by a MS trigger reverse layercolumn to obtain 9.6 mg (yield 14%) of compound 149.

¹H-NMR (CDCl₃) δ: 1.63 (3H, s), 2.95 (3H, s), 4.34 (1H, d, J=12.9 Hz),4.68 (1H, d, J=12.9 Hz), 5.21 (1H, s), 6.70 (1H, s), 7.18 (5H, s),7.37-7.47 (3H, m), 7.54 (2H, d, J=6.9 Hz).

Example 150

First Step

Compound 150A (465 mg, 0.801 mmol) synthesized according to the first tofourth step of Example 135 was dissolved in a 4N hydrochloric aciddioxane solution (5 ml), and the mixture was stirred at room temperaturefor 2 hours. The reaction solution was neutralized with saturated sodiumbicarbonate water, and was extracted with dichloromethane three times.After the extract was dried with sodium sulfate, the solvent wasdistilled off, and 100 mg of the resulting oil was dissolved indichloromethane (2 ml). To the dichloromethane solution were addedtriethylamine (63.2 mg, 0.624 mmol) and benzoyl chloride (31.9 mg, 0.312mmol) under ice-cooling, and the mixture was stirred at room temperaturefor 1 hour. To the reaction solution was added water, and the mixturewas extracted with dichloromethane three times. After the extract wasdried with sodium sulfate, the solvent was distilled off, and theresulting residue was washed with diethyl ether to obtain 68 mg (yield56%) of compound 150B.

¹H-NMR (CDCl₃) δ: 3.05-3.12 (1H, m), 3, 38-3.45 (1H, m), 3.64-3.70 (1H,m), 3.93-3.99 (1H, m), 4.22 (1H, d, J=13.2 Hz), 5.04 (1H, s), 5.07 (1H,d, J=13.2 Hz), 5.22 (1H, d, J=10.2 Hz), 5.31 (1H, d, J=10.2 Hz), 5.70(1H, d, J=7.8 Hz), 6.55 (1H, d, J=7.8 Hz), 6.98 (2H, d, J=6.6 Hz),7.08-7.19 (4H, m), 7.29-7.46 (5H, m), 7.49-7.53 (2H, m), 7.87 (2H, d,J=7.2 Hz), 8.06 (1H, brs).

Second Step

Compound 150B (30 mg, 0.051 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 15 mg (yield 59%) of compound 150.

¹H-NMR (CDCl₃) δ: 2.91-2.98 (1H, m), 3.54-3.66 (1H, m), 3.76-3.84 (1H,m), 4.13-4.18 (1H, m), 4.28 (1H, d, J=12.9 Hz), 5.11 (1H, s), 5.43 (1H,d, J=12.9 Hz), 5.45 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 7.10-7.18(4H, m), 7.35-7.47 (8H, m), 7.89 (2H, d, J=7.2 Hz), 8.41 (1H, s).

Example 151

According to Example 150, compound 151 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.69 (1H, br t, J=10.8 Hz), 3.40-3.49(1H, m), 3.06-3.74 (1H, m), 4.12-4.22 (1H, m), 4.20 (1H, d, J=12.9 Hz),5.08 (1H, s), 5.47 (1H, d, J=7.8 Hz), 5.50 (1H, d, J=12.9 Hz), 6.67 (1H,d, J=7.8 Hz), 7.12-7.21 (5H, m), 7.28-7.46 (5H, m), 8.31 (1H, brs).

Example 152

First Step

Compound 150A (50 mg, 0.801 mmol) was dissolved in a 4N hydrochloricacid dioxane solution (5 ml), and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was neutralized withsaturated sodium bicarbonate water, and was extracted withdichloromethane three times. After the extract was dried with sodiumsulfate, the solvent was distilled off, and 50 mg of the resulting oilwas dissolved in methanol (2 ml). To the methanol solution was added 10%Pd-C (10 mg), and the mixture was subjected to a catalytic reductionunder hydrogen stream. The catalyst was removed by filtration, and thefiltrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 10mg (yield 25%) of compound 152.

¹H-NMR (DMSO-d₆) δ: 2.74-2.78 (2H, m), 3.00-3.07 (1H, m), 3.78-3.85 (1H,m), 4.34 (1H, d, J=13.5 Hz), 5.13 (1H, d, J=13.5 Hz), 5.48-5.54 (1H, m),5.10 (1H, s), 7.20-7.47 (9H, m), 7.63-7.71 (2H, m).

Example 153

First Step

To a THF (3 ml) solution of compound 150A (30 mg, 0.052 mmol) was added10% Pd-C (10 mg), and the mixture was subjected to a catalytic reductionunder hydrogen stream. The catalyst was removed by filtration, and thefiltrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 20mg (yield 79%) of compound 153.

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 2.84-2.91 (1H, m), 3.18-3.25 (2H, m),4.03-4.11 (1H, m), 4.35 (1H, d, J-=13.2 Hz), 5.20 (1H, s), 5.24 (1H, d,J=13.2 Hz), 5.49 (1H, brs), 5.70 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8Hz), 7.16-7.20 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.2 Hz).

Example 154

First Step

To a DMF (10 ml) solution of compound 154A (539 mg, 1.01 mmol)synthesized according to the synthesis method of Example 65 were addedtriethylamine (615.7 mg, 6.08 mmol) and ethyl chlorocarbonate (328.8 mg,3.03 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 10 minutes. To the reaction solution were addedO,N-dimethylhydroxylamine hydrochloride (295.0 mg, 3.03 mmol) and DMAP(12.3 mg, 0.101 mmol), the mixture was stirred at the same temperaturefor 2 hours, water was added, and was extracted with ethyl acetate threetimes. After the extract was washed with water three times, and driedwith sodium sulfate, the solvent was distilled off, and the resultingoil was purified by silica gel chromatography. The materials were elutedfirstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with onlyethyl acetate. Concentration of an objective fraction afforded 445.4 mg(yield 76%) of compound 154B as an oil.

¹H-NMR (DMSO-d₆) δ: 3.09 (3H, s), 3.52 (3H, s), 3.94 (2H, s), 4.40 (1H,brs), 4.64 (2H, s), 4.96 (1H, brs), 5.15 (2H, s), 7.06-7.15 (4H, m),7.21 (2H, t, J=8.7 Hz), 7.28-7.38 (3H, m), 7.43 (2H, dd, J=5.7 Hz, 8.4Hz), 7.52-7.54 (2H, m), 7.66 (1H, s).

Second Step

A THF (5 ml) solution of compound 154B (250 mg, 0.435 mmol) was cooledto −78° C., a methylmagnesium bromide 0.97M THF solution (0.673 ml,0.653 mmol) was added, and temperature was raised to −20° C. over 2hours. To the reaction solution was added 1N hydrochloric acid, and themixture was extracted with ethyl acetate three times. After the extractwas dried with sodium sulfate, the solvent was distilled off, and theresulting oil was purified by silica gel chromatography. The materialswere eluted firstly with only chloroform and, then, withchloroform-methanol (7:3, v/v). Concentration of an objective fractionafforded 117.0 mg (yield 51%) of compound 154C as an oil.

¹H-NMR (CDCl₃) δ: 2.68 (3H, s), 3.80 (2H, brs), 4.29 (2H, brs), 4.71(2H, brs), 5.45 (2H, brs), 6.83 (2H, m), 6.92-6.98 (2H, m), 7.03-7.10(2H, m), 7.28-7.39 (5H, m), 7.90 (1H, s).

Third Step

To a dichloromethane (2 ml) solution of compound 154C (117 mg, 0.221mmol) was added mCPBA (52.7 mg, 0.332 mmol) under ice-cooling, and themixture was stirred at room temperature for 2 hours. To the reactionsolution was added an aqueous sodium thiosulfate solution, and themixture was extracted with ethyl acetate three times. After the extractwas washed with saturated sodium bicarbonate water two times, and driedwith sodium sulfate, the solvent was distilled off, the resulting oilwas dissolved in ethanol (2 ml), and the solution was refluxed for 1hour. After the solvent was distilled off, the precipitated solid waswashed with diisopropyl ether to obtain 54 mg (yield 49%) of compound154D.

¹H-NMR (CDCl₃) δ: 3.74 (1H, brs), 3.85 (1H, brs), 4.20 (2H, brs), 4.61(1H, brs), 4.93 (1H, brs), 5, 41 (2H, brs), 6.79-6.86 (2H, m), 6.91-6.96(2H, m), 7.02-7.09 (2H, m), 7.15-7.16 (1H, m), 7.26-7.34 (5H, m),7.56-7.65 (2H, m).

Fourth Step

To a THF (3 ml) solution of compound 154D (54 mg, 0.107 mmol) was added10% Pd-C (20 mg), and the mixture was subjected to a catalytic reductionunder hydrogen stream. The catalyst was removed by filtration, and thefiltrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 21mg (yield 47%) of compound 154.

¹H-NMR (DMSO-d₆) δ: 3.90 (2H, brs), 3.95 (2H, s), 4, 66 (2H, brs),7.07-7.12 (4H, m), 7.22 (2H, t, J=8.7 Hz), 7.29 (1H, s), 7.43-7.47 (2H,m).

Example 155

First Step

To a toluene (150 ml) solution of compound 155A (WO 2006/066414, 15.0 g,38.4 mmol) were sequentially added N,N-diisopropylethylamine (16.1 mL,92.0 mmol), 1-methylimidazole (3.70 mL, 46.4 mmol) and2-methoxyethylamine (4.05 mL, 46.4 mmol) under ice-cooling and,thereafter, diphenyl chlorophosphate (9.60 mL, 46.1 mmol) was furtheradded dropwise over 10 minutes. After the reaction solution was stirredfor 20 minutes under ice-cooling, acetonitrile (50 mL) was added, andthe mixture was further stirred for 2 hours. To the reaction solutionwas added an aqueous acetic acid solution (10%, 100 mL) underice-cooling and, thereafter, the mixture was extracted with ethylacetate. The extract was sequentially washed with water (100 mL),saturated sodium bicarbonate water (150 mL) and an aqueous saturatedsodium chloride solution (100 ml) and, thereafter, dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=25%→50%) to obtain compound 155B (7.86 g, 46%)as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.10 (6H, s), 0.93 (9H, s), 3.29 (3H, s), 3.39 (2H,m), 3.47 (2H, m), 4.56 (2H, d, J=1.2 Hz), 5.41 (2H, s), 6.60 (1H, s),7.35-7.42 (5H, m), 8.11 (1H, brt).

Second Step

To an ethanol (80 mL) solution of compound 155B (7.70 g, 17.2 mmol) wasadded aqueous ammonia (40 mL) at room temperature, and the mixture wasstirred for 18 hours. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=75%→100%) to obtain compound 155C(7.15 g, 93%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.14 (6H, s), 0.97 (9H, s), 3.28 (3H, s), 3.38 (2H,m), 3.49 (2H, m), 4.64 (2H, s), 5.53 (2H, s), 6.31 (1H, s), 7.34-7.49(5H, m), 8.61 (1H, brs), 9.94 (1H, brs).

Third Step

To a DMF (125 mL) solution of compound 155C (7.15 g, 16.0 mmol) andpotassium carbonate (6.64 g, 48.0 mmol) was addedO-(2,4-dinitrophenyl)hydroxylamine (7.97 g, 40.0 mmol) at roomtemperature, and the mixture was stirred for 2 days. To the reactionsolution was added water (250 mL) under ice-cooling and, thereafter, themixture was extracted with ethyl acetate (300 mL×2). After the extractwas sequentially washed with water (300 mL), saturated sodiumbicarbonate water (300 mL×2) and an aqueous saturated sodium chloridesolution (150 mL), the mixture was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography(methanol/chloroform=0%→10%) to obtain compound 155D (6.47 g, 88%) as apale yellow solid.

¹H-NMR (CDCl₃) δ: 0.11 (6H, s), 0.94 (9H, s), 3.26 (3H, s), 3.35 (4H,m), 4.66 (2H, s), 5.16 (2H, s), 5.24 (2H, s), 6.43 (1H, s), 7.31-7.40(5H, m), 7.59 (1H, brs).

Fourth Step

To a toluene (100 mL) solution of compound 155D (6.47 g, 14.0 mmol) andacetic acid (0.080 mL, 1.4 mmol) was added paraformaldehyde (0.422 g,14.1 mmol) at room temperature, and the mixture was stirred at 80° C.for 2 hours. The solvent was distilled off under reduced pressure, andthe resulting crude product of compound 155E was utilized in a next stepwithout purification.

Fifth Step

To a DMF (100 mL) solution of the crude product of compound 155Eobtained in the fourth step was added cesium carbonate (22.7 g, 69.8mmol) under ice-cooling, and the mixture was stirred for 1 hour. Underice-cooling, bromodiphenylmethane (5.20 g, 21.0 mmol) was added, and themixture was stirred at room temperature for 19 hours. To the reactionsolution was added water (200 mL) under ice-cooling and, thereafter, themixture was extracted with ethyl acetate (200 mL×3). The extract wassequentially washed with water (200 mL×2) and an aqueous saturatedsodium chloride solution (100 mL), and dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product of compound 155F was utilized in a next step withoutpurification.

MS: m/z=640 [M+H]⁺.

Sixth Step

To a methanol (100 mL) solution of the crude product of compound 155Fobtained in the fifth step was added hydrogen chloride (4N ethyl acetatesolution, 40 mL) at room temperature, and the mixture was stirred for2.5 hours. To the reaction solution was added an aqueous sodiumhydroxide solution (2N, 75 mL) to perform neutralization (pH=6) underice-cooling, and the mixture was extracted with chloroform (200 mL×3).The extract was dried with sodium sulfate, the solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (methanol/chloroform=5%→40%) to obtaincompound 155G (5.18 g, 3 step 70%) as an orange oil.

¹H-NMR (CDCl₃) δ: 3.16 (3H, s), 3.18-3.43 (3H, m), 3.60-3.74 (2H, m),4.06 (1H, d, J=13.5 Hz), 4.19 (1H, brs), 4.58 (1H, d, J=14.7 Hz), 5.00(1H, d, J=13.5 Hz), 5.24 (1H, s), 5.27 (2H, s), 5.96 (1H, s), 6.78 (2H,m), 6.98-7.10 (3H, m), 7.30-7.42 (8H, m), 7.72 (2H, m).

Seventh Step

To a THF (2 mL) solution of compound 155G (100 mg, 0.190 mmol),(bromomethyl)cyclopropane (0.110 mL, 1.12 mmol) and sodium iodide (5.0mg, 0.033 mmol) was added potassium tert-butoxide (78.0 mg, 0.695 mmol)at room temperature, the mixture was stirred at room temperature for 22hours and, thereafter, the mixture was stirred at 100° C. for 10 minutesunder microwave irradiation. To the reaction solution were added waterand hydrochloric acid (2N)(pH=1), the mixture was extracted withchloroform, and the extract was dried with sodium sulfate. The solventwas distilled off under reduced pressure, and the resulting crudeproduct of compound 155H was utilized in a next step withoutpurification.

MS: m/z=580 [M+H]⁺.

Eighth Step

To a DMF (2 mL) solution of the crude product of compound 155H obtainedin the seventh step was added lithium chloride (35.0 mg, 0.826 mmol) atroom temperature, and the mixture was stirred at 150° C. for 15 minutesunder microwave irradiation. The reaction solution was purified bypreparative LCMS to obtain compound 155 (4.3 mg, 2 step 5%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 0.16 (2H, m), 0.52 (2H, m), 0.98 (1H, m), 3.08 (3H,m), 3.20 (3H, s), 3.46 (2H, m), 3.68 (1H, dd, J=0.6, 14.1 Hz), 3.90 (1H,m), 4.52 (1H, d, J=13.2 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d,J=13.2 Hz), 5.38 (1H, s), 6.01 (1H, s), 6.98 (2H, m), 7.11-7.48 (8H, m).

MS: m/z=490 [M+H]⁺.

Example 156

According to Example 155, compound 156 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.4 Hz), 1.51 (2H, m), 3.15-3.23 (6H,m), 3.46 (2H, m), 3.69 (1H, dd, J=0.6, 14.1 Hz), 3.88 (1H, m), 4.54 (2H,d, J=14.1 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d, J=13.5 Hz), 5.39(1H, s), 6.12 (1H, s), 6.97 (2H, m), 7.12-7.47 (8H, m).

MS: m/z=478 [M+H]⁺.

Example 157

According to Example 155, compound 157 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 3.13-3.22 (1H, m), 3.18 (3H, s), 3.20 (3H, s),3.41-3.51 (2H, m), 3.60 (1H, d, J=13.8 Hz), 3.89 (1H, ddd, J=3.3 Hz, 4.2Hz, 14.4 Hz), 4.52 (1H, d, J=13.2 Hz), 4.53 (1H, d, J=13.8 Hz), 4.92(1H, d, J=13.2 Hz), 5.38 (1H, s), 5.98 (1H, s), 6.98 (2H, d, J=8.4 Hz),7.11-7.22 (3H, m), 7.36-7.48 (5H, m).

Example 158

First Step

To a THF (100 mL) solution of compound 155G (960 mg, 1.83 mmol) wasadded manganese dioxide (2.06 g, 92.0 mmol) at room temperature, and themixture was stirred for 2 days. After the reaction solution wasfiltered, the filtrate was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=60%→100%) to obtain compound 158A (554 mg, 58%)as a pale yellow foam.

¹H-NMR (CDCl₃) δ: 2.96 (1H, m), 3.18 (3H, s), 3.44 (2H, m), 4.18 (1H,m), 4.56 (1H, d, J′=13.8 Hz), 4.98 (1H, d, J=13.8 Hz), 5.28 (1H, s),5.54 (1H, d, J=10.5 Hz), 5.64 (1H, d, J=10.5 Hz), 6.35 (1H, s), 6.85(2H, m), 7.03 (2H, m), 7.18 (1H, m), 7.26-7.48 (8H, m), 7.64 (2H, m),10.10 (1H, s).

Second Step

To a methylene chloride (4 mL) solution of compound 158A (83.0 mg, 0.159mmol), pyrrolidine (0.0400 mL, 0.484 mmol) and acetic acid (0.100 ml)was added sodium triacetoxyborohydride (136 mg, 0.642 mmol) at roomtemperature, and the mixture was stirred for 28 hours. To the reactionsolution was added water, the mixture was extracted with chloroform, andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product of compound 158Bwas utilized in a next step without purification.

MS: m/z=579 [M+H]⁺.

Third Step

To a DMF (2 mL) solution of the crude product of compound 158B obtainedin the second step was added lithium chloride (39.2 mg, 0.925 mmol) atroom temperature, and the mixture was stirred at 150° C. for 15 minutesunder microwave irradiation. The reaction solution was distilled offunder reduced pressure, and the resulting residue was purified bypreparative LCMS to obtain compound 158 (8.8 mg, 2 step 11%) as a yellowoil.

¹H-NMR (CDCl₃) δ: 1.84 (4H, m), 2.70-2.85 (5H, m), 3.19 (3H, s),3.20-3.47 (3H, m), 3.80 (1H, m), 4.25 (1H, d, J=14.7 Hz), 4.57 (1H, d,J=13.5 Hz), 5.07 (1H, d, J=13.5 Hz), 5.39 (1H, s), 6.06 (1H, s), 6.97(2H, m), 7.12-7.54 (8H, m), 8.29 (1H, s).

MS: m/z=489 [M+H]⁺.

Example 159

First Step

To a methylene chloride (20 mL) solution of compound 155G (950 mg, 1.81mmol) and N,N-diisopropylethylamine (0.380 mL, 2.18 mmol) was addeddropwise methanesulfonyl chloride (0.148 mL, 1.90 mmol) underice-cooling, and the mixture was stirred for 90 minutes. To the reactionsolution was added water (20 mL), the mixture was extracted withchloroform (50 mL), and the extract was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product (1.06 g) of compound 159A was utilized in a next stepwithout purification.

MS: m/z=604 [M+H]⁺.

Second Step

To the crude product (161 mg) of compound 159A obtained in the firststep was added dimethylamine (2M THF solution, 2.00 mL, 4.00 mmol) atroom temperature, and the mixture was stirred for 3 days. To thereaction solution was added an aqueous saturated sodium chloridesolution (2 mL), the mixture was extracted with ethyl acetate, and theextract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude-product of compound 159Bwas utilized in a next step without purification.

MS: m/z=553 [M+H]⁺.

Third Step

To a DMF (2 mL) solution of the crude product of compound 159B obtainedin the second step was added lithium chloride (56.0 mg, 1.32 mmol) atroom temperature, and the mixture was stirred at 150° C. for 30 minutesunder microwave irradiation. The reaction solution was distilled offunder reduced pressure, and the resulting residue was purified bypreparative LCMS to obtain compound 159 (33.6 mg, 3 step 27%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 2.69 (1H, d, J=14.4 Hz), 3.19 (3H, s),3.30-3.46 (3H, m), 3.76 (1H, m), 4.00 (1H, d, J=14.4 Hz), 4.60 (1H, d,J=13.5 Hz), 5.20 (1H, d, J=13.5 Hz), 5.40 (1H, s), 6.01 (1H, s), 6.97(2H, m), 7.11-7.42 (8H, m).

MS: m/z=463 [M+H]⁺.

Example 160

First Step

To a crude product (95.8 mg) of compound 159A was added methylamine (2MTHF solution, 2.00 mL, 4.00 mmol) at room temperature, and the mixturewas stirred for 3 days. The reaction solution was filtered, the solventwas distilled off under reduced pressure, and the resulting crudeproduct of compound 160A was utilized in a next step withoutpurification.

MS: m/z=539 [M+H]⁺.

Second Step

To an acetonitrile (3 mL) suspension of the crude product of compound160A and sodium iodide (100 mg, 0.667 mmol) was addedchlorotrimethylsilane (0.0850 mL, 0.665 mmol) at room temperature, andthe mixture was stirred for 5 hours. To the reaction solution was addedwater (1 mL), the solvent was distilled off under reduced pressure, andthe resulting residue was purified by preparative LCMS to obtaincompound 160 (59.8 mg, 3 step 84%) as a white solid.

¹H-NMR (CDCl₃) δ: 2.75 (3H, s), 3.08 (1H, d, J=13.5 Hz), 3.24 (3H, s),3.30-3.40 (3H, m), 3.75 (1H, m), 4.32 (1H, d, J=13.8 Hz), 4.66 (1H, d,J=13.8 Hz), 5.33 (1H, s), 5.58 (1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98(2H, m), 7.12-7.25 (3H, m), 7.40-7.51 (2H, m), 7.60 (2H, m).

MS: m/z=449 [M+H]⁺.

Example 161

First Step

After a DMF (2 mL) suspension of a crude product (156 mg) of compound159A, imidazole (19.5 mg, 0.286 mmol) and potassium carbonate (37.7 mg,0.273 mmol) was stirred at room temperature for 4 hours, sodium hydride(60%, 11.7 mg, 0.293 mmol) was added, and the mixture was stirred for 3days. To the reaction solution was added an aqueous acetic acid solution(10%), the mixture was extracted with chloroform, and the extract wasdried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product of compound 161A was utilizedin a next step without purification.

MS: m/z=576 [M+H]⁺.

Second Step

To the crude product of compound 161A was added trifluoroacetic acid (1mL) at room temperature, and the mixture was stirred for 18 hours and,thereafter, the mixture was stirred at 60° C. for 3 hours. The reactionsolution was distilled off under reduced pressure, and the resultingresidue was purified by preparative LCMS to obtain compound 161 (19.8mg, 3 step 16%) as a pale orange amorphous substance.

¹H-NMR (CDCl₃) δ: 3.17-3.25 (1H, m), 3.21 (3H, s), 3.38-3.47 (2H, m),3.82 (1H, m), 4.40 (1H, d, J=16.5 Hz), 4.54 (1H, d, J=13.5 Hz), 5.02(1H, d, J=13.5 Hz), 5.09 (1H, s), 5.32 (1H, d, J=16.5 Hz), 5.40 (1H, s),6.65 (1H, brs), 7.03 (2H, m), 7.15-7.49 (8H, m), 8.08 (1H, brs).

MS: m/z=486 [M+H]⁺.

Example 162

First Step

To a DMF (2 mL) solution of a crude product (192 mg) of compound 159Awas added sodium azide (24.2 mg, 0.372 mmol) at room temperature, andthe mixture was stirred at 60° C. for 2 hours. The reaction solution wasdistilled off under reduced pressure, and the resulting crude product ofcompound 162A was utilized in a next step without purification.

MS: m/z=551 [M+H]⁺.

Second Step

To a THF (4 mL) solution of the crude product of compound 162A weresequentially added water (0.200 mL) and triphenylphosphine (83.0 mg,0.316 mmol) at room temperature, and the mixture was stirred at 60° C.for 1 hour. The reaction solution was distilled off under reducedpressure, and the resulting residue was purified by preparative LCMS toobtain compound 162B (110 mg, 3 step 66%) as a colorless oil.

MS: m/z=525 [M+H]⁺.

Third Step

To an acetonitrile (1 mL) suspension of compound 162B (50.0 mg, 0.0950mmol) and sodium iodide (56.2 mg, 0.375 mmol) was addedchlorotrimethylsilane (0.0490 mL, 0.381 mmol) at room temperature, andthe mixture was stirred for 6 hours. To the reaction solution was addedwater (0.5 mL), the solvent was distilled off under reduced pressure,and the resulting residue was purified by preparative LCMS to obtaincompound 162 (25.9 mg, 63%) as a pale orange solid.

¹H-NMR (CDCl₃) δ: 3.12 (1H, d, J=14.7 Hz), 3.27 (3H, s), 3.35-3.48 (3H,m), 3.81 (1H, m), 4.65 (1H, d, J=13.5 Hz), 5.31 (1H, s), 5.59 (1H, d,J=13.5 Hz), 6.40 (1H, s), 6.98 (2H, m), 7.19 (3H, m), 7.40 (1H, m), 7.50(2H, m), 7.62 (2H, m), 8.11 (1H, s).

MS: m/z=435 [M+H]⁺.

Example 163

First Step

To an acetonitrile (3 mL) solution of compound 162B (50.0 mg, 0.0950mmol) and N,N-diisopropylethylamine (0.0366 mL, 0.210 mmol) was addedacetic anhydride (0.0100 mL, 0.106 mmol) at room temperature, and themixture was stirred for 6 hours. The reaction solution was distilled offunder reduced pressure, and the resulting crude product of compound 163Awas utilized in a next step without purification.

MS: m/z=567 [M+H]⁺.

Second Step

To an acetonitrile (5 mL) suspension of the crude product of compound163A and sodium iodide (59.2 mg, 0.395 mmol) was addedchlorotrimethylsilane (0.0487 mL, 0.381 mmol) at room temperature, andthe mixture was stirred for 16 hours. To the reaction solution was addedwater (0.5 mL), the solvent was distilled off under reduced pressure,and the resulting residue was purified by preparative LCMS to obtaincompound 163 (28.1 mg, 2 step 62%) as a pale orange foam.

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 3.24 (3H, s), 3.27-3.52 (4H, m), 3.67(1H, m), 4.54 (1H, d, J=13.5 Hz), 4.78 (1H, dd, J=6.5, 14.9 Hz), 5.17(1H, d, J=13.5 Hz), 5.28 (1H, s), 5.61 (1H, s), 7.01 (2H, m), 7.01-7.58(9H, m).

MS: m/z=477 [M+H]⁺.

Example 164

First Step

Compound 155G (43.3 mg, 0.221 mmol) was dissolved in trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.The solvent was distilled off, the residue was dissolved indichloromethane (2 ml), and the solution was neutralized with saturatedsodium bicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 22 mg (yield 61%) of compound 164.

¹H-NMR (CDCl₃) δ: 1.13 (6H, d, J=6.0 Hz), 3.18-3.77 (7H, m), 3.26 (3H,s), 4.49 (1H, d, J=12.3 Hz), 4.76 (1H, d, J=12.3 Hz), 5.27 (2H, brs),5.89 (1H, s), 6.90 (2H, d, J=7.2 Hz), 6.98-7.14 (3H, m), 7.315-7.50 (5H,m).

Example 165

First Step

To a DMF (370 mL) solution of compound 165A (WO 2006/088173, 37.0 g, 108mmol) were sequentially added potassium carbonate (17.9 mg, 129 mmol)and methyl iodide (8.03 mL, 129 mmol) at room temperature, and themixture was stirred for 1.5 hours. The reaction solution was added to asolution of ammonium chloride (20.8 g, 390 mmol) in water (1110 mL)under ice-cooling, and the precipitated solid was filtered, and washedwith water to obtain a crude product (33 g). In addition, the aqueouslayer was salted out with sodium chloride, and the mixture was extractedwith ethyl acetate, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and a crude product (9 g) wasobtained from the resulting residue. The crude products were combinedand purified by silica gel column chromatography (ethylacetate/n-hexane=50%→100%) to obtain compound 165B (36.5 g, 95%) as awhite solid.

Second Step

To a 1,4-dioxane (548 mL) solution of compound 165B (36.5 g, 102 mmol)were sequentially added potassium osmate dihydrate (1.13 g, 3.06 mmol),sodium periodate (87.3 g, 408 mmol) and water (365 mmol) at roomtemperature, and the mixture was stirred for 6 hours. The reactionsolution was extracted with methylene chloride, and the extract wasdried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=50%→100%) to obtain compound 165C(33.0 g, 90%) as a bronzed foam.

Third Step

To a toluene (25 mL) suspension of compound 165C (1.38 g, 3.66 mmol)were sequentially added ethylenediamine (0.247 mL, 3.66 mmol) and aceticacid (0.0210 mL, 0.366 mmol) at room temperature and, thereafter, themixture was stirred for 1 hour, and further stirred at 50° C. for 17hours. The precipitated solid was filtered, and washed with ether toobtain compound 165D (1.11 g, 100%) as a pale yellow solid.

¹HNMR (DMSO-d₆) δ: 3.05 (2H, m), 3.26 (1H, m), 3.63 (2H, m), 3.75 (3H,s), 3.87 (1H, m), 4.52 (1H, dd, J=3.3, 12.6 Hz), 4.69 (1H, m), 4.99 (1H,d, J=10.4 Hz), 5.15 (1H, d, J=10.4 Hz), 7.35 (3H, m), 7.54 (2H, m), 8.41(1H, s).

Fourth Step

To an acetonitrile (30 mL) suspension of compound 165D (2.77 g, 7.50mmol), potassium carbonate. (2.23 g, 16.1 mmol) and sodium iodide (102mg, 0.680 mmol) was added bromodiphenylmethane (2.26 g, 9.14 mmol) atroom temperature, and the mixture was stirred at 90° C. for 7 hours. Thereaction solution was poured into hydrochloric acid (2N, 10 mL) and anice (20 g), the mixture was extracted with chloroform (100 mL×2), andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (chloroform/methanol=0%→5%) to obtain compound165E (2.72 g, 68%) as a pale yellow solid.

Fifth Step

To an ethanol (30 mL) solution of compound 165E (2.72 g, 5.08 mmol) wasadded an aqueous sodium hydroxide solution (2N, 10 mL) at roomtemperature, and the mixture was stirred for 3 days. To the reactionsolution was added hydrochloric acid (1N, 20 mL) (pH=1) at roomtemperature, the mixture was extracted with chloroform (100 mL×2), andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (chloroform/methanol=0%→10%) to obtaincompound 165F (1.77 g, 67%) as a pale yellow solid.

¹HNMR (DMSO-d₆) δ: 2.63 (1H, m), 3.16 (1H, m), 3.49 (1H, m), 3.73 (1H,m), 4.12 (2H, m), 4.56 (1H, m), 5.04 (1H, s), 5.09 (1H, d, J=10.7 Hz),5.19 (1H, d, J=10.7 Hz), 7.28-7.53 (15H, m), 8.32 (1H, s), 8.39 (1H, s).

Sixth Step

A N,N′-dimethylimidazolidinone (20 mL) solution of compound 165F (1.77g, 3.39 mmol) and lithium chloride (0.515 g, 12.2 mmol) was stirred at90° C. for 1 hour. To the reaction solution were sequentially addedwater (10 mL), hydrochloric acid (2N, 10 mL) and water (10 mL) at roomtemperature. The precipitated solid was filtered, and washed with ether,DMF-water were added, and the precipitated solid was filtered to obtaincompound 165 (599 mg, 41%) as a white solid.

¹HNMR (DMSO-d₆) δ: 2.60 (1H, m), 3.20 (1H, m), 3.64 (2H, m), 4.00 (2H,m), 4.55 (1H, m), 5.01 (1H, s), 7.28-7.47 (10H, m), 8.16 (1H, s), 11.97(1H, brs).

MS: m/z=432 [M+H]⁺.

Example 166

According to Example 165, following compound 166 was synthesized by thesame procedure.

¹HNMR (DMSO-d₆) δ: 1.54 (1H, d, J=12.6H), 1.66-1.78 (1H, m), 2.60 (1H,t, J=9.9 Hz), 2.83 (1H, d, J=11.7 Hz), 3.01 (1H, t, J=11.7 Hz),3.34-3.38 (1H, m), 3.94 (1H, d, J=13.8 Hz), 4.44-4.59 (3H, m), 4.82 (1H,d, J=14.7 Hz), 7.06 (2H, t, J=8.7 Hz), 7.18-7.23 (2H, m), 8.27 (1H, s),12.84 (1H, brs).

Example 167

First Step

To a xylene (30 ml) solution of compound 167A (WO 2006/11674, 3.58 g,7.61 mmol) were added (S)—N1-benzyl-3-phenylpropane-1,2-diamine (Journalof the American Chemical Society; English; 127; 30; 2005; 10504, 1.83 g,7.61 mmol) and acetic acid (0.5 ml), and the mixture was refluxed for 2hours. After cooling to room temperature, the solvent was distilled off,and the resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (9:1, v/v)and, then, with n-hexane-ethyl acetate (1:1, v/v). Concentration of anobjective fraction afforded 349 mg (yield 7%) of compound 167B as anoil.

¹HNMR (CDCl₃) δ: 2.54 (1H, t, J=9.6 Hz), 2.77 (1H, dd, J=9.0 Hz, 13.2Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.43-3.78 (5H, m), 4.04-4.15 (1H,m), 4.42-4.48 (1H, m), 4.62 (2H, d, J=6.0 Hz), 5.29 (1H, d, J=10.5 Hz),5.43 (1H, d, J=10.5 Hz), 6.77-6.85 (2H, m), 7.19-7.39 (14H, m), 7.60(2H, d, J=6.3 Hz), 8.05 (1H, s).

Second Step

To a MeCN (10 ml) solution of compound 167B (968 mg, 1.47 mmol) wereadded Boc₂O (3 ml) and DMAP (180 mg, 1.47 mmol), and the mixture washeated to reflux for 5 hours. To the reaction solution was added a 2Naqueous sodium hydroxide solution to stop the reaction, the reactionsolution was neutralized using 2N hydrochloric acid and, thereafter, themixture was extracted with ethyl acetate three times. After the extractwas washed with an aqueous saturated sodium chloride solution, thesolvent was distilled off, and the resulting oil was purified by silicagel chromatography. The materials were eluted firstly withn-hexane-ethyl acetate (6:4, v/v) and, then, only with ethyl acetate.Concentration of an objective fraction afforded 349 mg (yield 45%) ofcompound 167C.

¹HNMR (CDCl₃) δ: 2.54 (1H, t=9.0 Hz), 2.76 (1H, dd, J=9.3 Hz, 16.5 Hz),3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.45 (1H, dd, J=3.3 Hz, 12.6 Hz),3.51-3.78 (4H, m), 4.04-4.13 (1H, m), 4.42-4.52 (1H, m), 4.61 (2H, d,J=6.0 Hz), 2.79 (1H, d, J=10.2 Hz), 5.29 (1H, d, J=10.2 Hz), 5.43 (1H,d, J=10.2 Hz), 6.76-7.39 (11H, m), 7.60 (2H, d, J=6.6 Hz), 8.05 (1H, s),10.42 (1H, t, J=5.7 Hz).

Third Step

Compound 167C (150 mg, 0.280 mmol) was dissolved in trifluoroacetic acid(2 ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 71 mg (yield 57%) of compound 167.

¹HNMR (CDCl₃) δ: 2.65 (1H, dd, J=8.4 Hz, 9.6 Hz), 2.97 (1H, dd, J=9 Hz,13.5 Hz), 3.43 (1J, dd, J=7.2 Hz, 9.6 Hz), 3.55 (1H, dd, J=3.0 Hz, 13.2Hz), 3.61-3.80 (4H, m), 4.15 (1H, dd, J=4.2 Hz, 9.9 Hz), 4.51-4.60 (1H,m), 7.15-7.18 (2H, m), 7.28-7.38 (8H, m), 8.02 (1H, s), 12.04 (1H, s).

Example 168

First Step

To a DMF (3 mL) solution of compound 168A (WO 2006/116764, 400 mg, 0.840mmol) were added cesium carbonate (821 mg, 2.52 mmol) and, subsequently,bromomethylenedibenzene (311 mg, 1.26 mmol), and the mixture was stirredat 100° C. for 5 hours. To the reaction solution were added 2Nhydrochloric acid, water and ethyl acetate, the ethyl acetate layer wasseparated, and the aqueous layer was extracted with ethyl acetate once.The combined extracts were washed with an aqueous saturated sodiumbicarbonate solution and brine, dried with magnesium sulfate, filteredand concentrated. The resulting residue was purified by silica gelcolumn chromatography. Concentration of an objective fraction afforded100 mg of compound 168B as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.79-1.84 (2H, m), 2.67-2.77 (1H, m), 2.84-3.05 (2H,m), 4.03 (1H, dd, J=13.0, 4.2 Hz), 4.28 (1H, dd, J=13.6, 6.5 Hz), 4.49(1H, dd, J=6.4, 3.8 Hz), 4.57 (2H, d, J=5.7 Hz), 4.78 (1H, dd, J=13.4,5.7 Hz), 4.93 (1H, s), 5.27 (2H, s), 7.00 (2H, t, J=8.8 Hz), 7.15-7.37(14H, m), 7.57-7.63 (2H, m), 7.76 (1H, s), 10.44 (1H, t, J=5.9 Hz).

MS: m/z=643.20 [M+H]⁺.

Second Step

Compound 168B (100 mg, 0.156 mmol) was dissolved in acetonitrile (3 mL),Boc₂O (4.0 mL, 17.3 mmol) and, subsequently, DMAP (84 mg, 0.69 mmol)were added, and the mixture was stirred at 80° C. for 6 hours. Thereaction solution was allowed to cool, a 2N aqueous sodium hydroxidesolution (8 mL) and, subsequently, ethanol (3 mL) were added, and themixture was stirred at 60° C. for 2 hours. To the reaction solution wereadded 2N hydrochloric acid and ethyl acetate, the ethyl acetate layerwas separated, and the aqueous layer was extracted with ethyl acetate.The solvent was distilled off, and the resulting residue was purified bysilica gel chromatography. Elution with ethyl acetate-methanol, andconcentration of an objective fraction afforded 84 mg of compound 168C.

MS: m/z=536.25 [M+H]⁺.

Third Step

To a DMI (2 mL) solution of compound 168C (80 mg, 0.15 mmol) was addedlithium chloride (19 mg, 0.45 mmol), and the mixture was stirred at 90°C. for 2 hours. To the reaction mixture were added water and 2Nhydrochloric acid, the precipitated solid was filtered, and theresulting solid was purified using a LCMS fractionating device. Theeluted solvent was distilled off, to the residue was added isopropylether, and the precipitated solid was filtered. Washing with isopropylether and drying afforded 12 mg of compound 168.

MS: m/z=446.05 [M+H]⁺.

Example 169

First Step

To an ethanol (5 mL) solution of compound 95A (WO 2006/116764, 500 mg,2.03 mmol) was added 2,2-dimethoxyethanamine (0.49 ml, 4.47 mmol), andthe mixture was stirred at 80° C. for 3 hours. After the reactionsolution was allowed to cool, acetic acid (0.27 ml, 4.69 mmol) was addedat room temperature, and the mixture was concentrated under reducedpressure. The resulting residue was dissolved in DMF (5 mL), DBU (0.66mL, 4.4 mmol) and, subsequently, methyl iodide (1.02 mL, 16.2 mmol) wereadded under nitrogen atmosphere, and the mixture was stirred at roomtemperature for 3 hours. To the reaction solution were added an aqueoussaturated sodium bicarbonate solution and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered and concentrated, and the resulting residue waspurified by silica gel chromatography. Elution with chloroform-methanol(9:1) and concentration of an objective fraction afforded 258 mg ofcompound 169A as a brown oil.

¹H-NMR (CDCl₃) δ: 3.37 (6H, s), 3.80 (3H, s), 3.87 (2H, d, J=4.8 Hz),4.46 (1H, t, J=4.8 Hz), 5.30 (2H, s), 6.75 (1H, d, J=6.0 Hz), 7.30-7.41(6H, m).

Second Step

To compound 169A (1.00 g, 2.88 mmol) were added formic acid (31 mL) and,subsequently, water (5 mL), and the mixture was stirred at 70° C. for6.5 hours. To the reaction mixture were added water and ethyl acetate,the ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. After the combined extracts were washedwith an aqueous saturated sodium bicarbonate solution, and sodiumsulfate was added, then the mixture was filtered and concentrated, andthe resulting residue was purified by silica gel chromatography. Elutionwith ethyl acetate-methanol, and concentration of an objective fractionafforded a mixture of aldehyde hydride and methylacetal as a colorlesstransparent oil. The resulting oil was dissolved in dichloromethane (5mL), 1,3-diaminopropane dihydrochloride (354 mg, 2.41 mmol) and,subsequently, acetic acid (0.069 ml, 1.2 mmol) were added, and themixture was stirred at room temperature for 6 hours. The reactionsolution was diluted with dichloromethane, insolubles were filtered and,thereafter, the mixture was concentrated under reduced pressure toobtain a crude purified product of compound 169B.

MS: m/z=326.20 [M+H]⁺.

Third Step

To an acetonitrile (4 mL) solution of compound 168B (391 mg, 1.20 mmol)were added potassium carbonate (498 mg, 3.61 mmol) and, subsequently,bromomethylenedibenzene (890 mg, 3.61 mmol). After the reaction solutionwas stirred at 90° C. for 2 hours, to the reaction solution were addedwater, ethyl acetate and brine, the ethyl acetate layer was separated,and the aqueous layer was extracted with ethyl acetate once. After thecombined extracts were dried with magnesium sulfate, then the mixturewas filtered and concentrated. The resulting residue was purified bysilica gel column chromatography. Elution with ethyl acetate-methanol,and concentration of an objective fraction afforded 106 mg of compound169C as an orange solid.

MS: m/z=492.15 [M+H]⁺.

Fourth Step

To a DMI (2 mL) solution of compound 169C (105 mg, 0.214 mmol) was addedlithium chloride (27.2 mg, 0.641 mmol), and the mixture was stirred at900° C. for 3 hours. Further, lithium chloride (27.2 mg, 0.641 mmol) wasadded, and the mixture was stirred at 90° C. for 1 hour. The reactionsolution was concentrated under reduced pressure, and the resultingresidue was purified using a LCMS fractionating device. The elutedsolvent was distilled off, to the residue was added diethyl ether, andthe precipitated solid was filtered. Washing with diethyl ether, anddrying afforded 27 mg of compound 169.

¹H-NMR (CD₃OD) δ: 1.63 (1H, dd, J=13.4, 2.8 Hz), 1.84 (1H, br s),2.55-2.64 (1H, m), 2.90-3.10 (2H, m), 4.30 (1H, dd, J=14.5, 4.0 Hz),4.52 (4H, dd, J=14.5, 3.8 Hz), 4.63-4.75 (4H, m), 5.16 (1H, s), 6.16(1H, d, J=7.2 Hz), 6.78 (1H, d, J=7.2 Hz), 7.16-7.32 (10H, m).

MS: m/z=402.10 [M+H]⁺.

Example 170

First Step

Compound 49F (87 mg, 0.19 mmol) was dissolved in ethanol (1 ml) and THF(1 ml), a 2N aqueous sodium hydroxide solution (0.47 ml, 0.95 mmol) wasadded, and the mixture was stirred at room temperature for 1.5 hours. Tothe reaction solution was added 2N hydrochloric acid, the mixture wasextracted with ethyl acetate, and the extract was dried with sodiumsulfate. The resulting crude product was purified by silica gel columnchromatography (chloroform-methanol 95:5→90:10, v/v) to obtain 60 mg ofcompound 170A.

¹H-NMR (CDCl₃) δ: 2.48 (1H, dd, J=13.8, 11.8 Hz), 3.27 (1H, dd, J=14.2,3.4 Hz), 3.73-3.80 (1H, m), 3.92 (1H, m), 4.16 (1H, m), 4.45 (2H, m),5.34 (1H, d, J=3.5 Hz), 5.47 (1H, d, J=10.4 Hz), 5.52 (1H, d, J=10.7Hz), 6.73 (2H, d, J=6.9 Hz), 7.18-7.42 (7H, m), 7.60 (2H, d, J=6.9 Hz),14.63 (1H, s).

Second Step

To compound 170A (57 mg, 0.13 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 3 with sodiumbicarbonate water and 2N hydrochloric acid, then the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 19 mg of compound 170 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.74 (1H, t, J=12.1 Hz), 3.10-3.22 (1H, m), 3.76(2H, m), 4.12 (1H, q, J=8.0 Hz), 4.44 (1H, m), 5.35 (1H, m), 5.49 (1H,d, J=3.4 Hz), 7.05 (5H, m), 7.77 (1H, s), 12.05 (1H, brs).

Example 171

First Step

Compound 49B (950 mg, 3.35 mmol), 3-aminopropan-1-ol (277 mg, 3.69 mmol)and sodium sulfate (1.91 g, 13.4 mmol) were added to toluene (25 ml),and the mixture was stirred at room temperature for 1 hour. Boc₂O (0.856ml, 3.69 mmol) was added at room temperature, and the mixture wasstirred for 18 hours. Further, Boc₂O (0.400 ml, 1.72 mmol) was added atroom temperature, and the mixture was stirred for 60 hours. The reactionsolution was filtered, and the filtrate was concentrated under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.02 g ofcompound 171A as a colorless gummy substance.

Second Step

Compound 171A (1.01 g, 2.29 mmol) and palladium-active carbon (10%, wet,200 mg) were added to ethanol (20 ml), and the mixture was stirred atroom temperature for 1.5 hours under hydrogen atmosphere. Afterfiltration with celite, the solvent was concentrated under reducedpressure to obtain 755 mg of a colorless oily substance 171B.

¹H-NMR (CDCl₃) δ: 1.42 (5H, s), 1.49 (4H, s), 1.56-1.92 (2H, m), 2.49(0.4H, dd, J=13.6, 9.8 Hz), 2.62 (0.6H, dd, J=13.6, 8.5 Hz), 2.81 (0.4H,dd, J=13.5, 3.6 Hz), 3.16 (1.6H, m), 3.60-4.14 (4H, m), 5.13 (0.6H, d,J=8.8 Hz), 5.19 (0.4H, d, J=8.5 Hz), 7.22-7.37 (5H, m).

Third Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (660 mg, 1.99mmol) and compound 171B (609 mg, 1.99 mmol) were added to toluene (8ml), and the mixture was stirred at 100° C. for 1.5 hours. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 99:1, v/v) to obtain 1.02 g of compound 171C as apale yellow gummy substance.

Fourth Step

To compound 171C (991 mg, 1.60 mmol) was added 4N HCl (ethyl acetatesolution, 12 ml). After the mixture was stirred at room temperature for1 hour, the solvent was distilled off under reduced pressure.Subsequently, toluene (12 ml) and 3-aminopropan-1-ol (0.244 ml, 3.19mmol) were added, the mixture was stirred at 80° C. for 10 minutes.After the solvent was distilled off under reduced pressure, theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 99:1→95:5→90:10, v/v) to obtain 341 mg of compound171D as a yellow gummy substance and 338 mg of compound 171E as acolorless solid.

171D: ¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 1.51 (1H, d, J=13.7 Hz),1.97 (1H, m), 2.91 (1H, dd, J=13.8, 9.8 Hz), 2.99-3.10 (2H, m), 3.90(1H, td, J=12.1, 2.5 Hz), 4.12 (2H, m), 4.25 (2H, m), 4.83 (2H, m), 5.33(1H, d, J=10.1 Hz), 5.51 (1H, d, J=10.1 Hz), 6.88 (2H, m), 7.23-7.40(7H, m), 7.68 (2H, m)

171E: ¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J=7.2 Hz), 1.82-1.99 (2H, m), 2.73(1H, dd, J=14.0, 11.3 Hz), 3.13 (1H, m), 3.35 (1H, dd, J=14.0, 3.4 Hz),3.63 (1H, m), 3.90-4.26 (4H, m), 4.43 (1H, d, J=13.6 Hz), 5.27 (1H, t,J=3.5 Hz), 5.31 (2H, s), 6.78 (2H, dd, J=6.3, 3.2 Hz), 7.01 (1H, d,J=7.0 Hz), 7.18 (3H, t, J=3.1 Hz), 7.28-7.39 (3H, m), 7.67 (2H, m).

Fifth Step

Compound 171D (329 mg, 0.673 mmol) was dissolved in ethanol (2 ml) andTHF (4 ml), a 2N aqueous sodium hydroxide solution (1.69 ml, 3.38 mmol)was added, and the mixture was stirred at room temperature for 1 hour.To the reaction solution was added 2N hydrochloric acid, the mixture wasextracted with ethyl acetate, and the extract was dried with sodiumsulfate. The solvent was concentrated under reduced pressure to obtain215 mg of compound 171F as a colorless solid.

MS: m/z=461 [M+H]⁺.

Sixth Step

To compound 171F (50 mg, 0.11 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, the mixture was extractedwith chloroform, and the extract was dried with sodium sulfate. Afterthe solvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 24 mg of compound 171 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.63 (1H, d, J=12.6 Hz), 1.83 (1H, m), 2.96-3.29(3H, m), 4.05 (2H, m), 4.55 (1H, dd, J=13.2, 4.4 Hz), 5.08 (1H, dd,J=9.2, 5.4 Hz), 5.30 (1H, s), 7.19 (5H, m), 8.09 (1H, s), 12.84 (1H,brs).

MS: m/z=371 [M+H]⁺.

Example 172

According to Example 171, using compound 171E, compound 172 wassynthesized by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.91 (2H, m), 2.94 (1H, dd, J=14.0, 10.8 Hz),3.11-3.21 (3H, m), 3.71 (1H, m), 4.19 (1H, m), 4.29-4.35 (1H, m),5.08-5.14 (1H, m), 5.47 (1H, d, J=4.0 Hz), 6.92-7.22 (5H, m), 7.71 (1H,s), 12.80 (1H, brs), 15.06 (1H, brs).

MS: m/z=371 [M+H]⁺.

Example 173

First Step

Compound 171F (159 mg, 0.345 mmol) was added to diphenyl ether (2.5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,95:5→90:10, v/v) to obtain compound 173A.

Second Step

To compound 173A obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 10 mg of compound 173 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.55-1.86 (2H, m), 2.84-3.26 (3H, m), 3.92-4.09 (2H,m), 4.55 (2H, m), 5.15 (1H, s), 5.89 (1H, d, J=7.5 Hz), 7.17 (6H, m),12.11 (1H, brs)

MS: m/z=327 [M+H]⁺.

Example 174

According to Example 173, compound 174 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.86 (2H, m), 2.87 (1H, t, J=12.3 Hz), 3.18 (2H, m),3.68 (1H, t, J=10.4 Hz), 4.16 (1H, d, J=10.1 Hz), 4.29 (1H, d, J=12.4Hz), 4.71 (1H, d, J=9.2 Hz), 5.37 (1H, d, J=3.5 Hz), 5.75 (1H, d, J=7.5Hz), 7.00 (6H, m), 12.51 (1H, brs).

MS: m/z=327 [M+H]⁺.

Example 175

First Step

To Dess-Martin Periodinane (0.3M, methylene chloride solution, 25.0 ml,7.50 mmol) was added dropwise a methylene chloride solution (10 ml) ofcompound 2B (1.98 g, 5.48 mmol) at 0° C. After the mixture was stirredat room temperature for 3 hours, the mixture was poured into a 1Naqueous sodium hydroxide solution, and extracted with ethyl ether. Theorganic layer was washed with a 1N aqueous sodium hydroxide solution andan aqueous saturated sodium chloride solution, and dried with magnesiumsulfate. After the solvent was distilled off under reduced pressure,purification was performed by silica gel column chromatography(n-hexane-ethyl acetate, 2:1, v/v) to obtain 1.73 g of compound 175A asa white solid.

¹H-NMR (CDCl₃) δ: 4.55 (1H, d, J=7.3 Hz), 5.09 (2H, s), 5.14 (2H, m),7.22-7.35 (15H, m), 9.62 (1H, s).

Second Step

Compound 175A (1.30 g, 4.59 mmol), 3-aminopropan-1-ol (379 mg, 5.05mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added to toluene (40ml), and the mixture was stirred at room temperature for 1 hour. Boc₂O(1.17 ml, 5.05 mmol) was added at room temperature, and the mixture wasstirred for 18 hours. Boc₂O (1.17 ml, 5.05 mmol) and sodium sulfate(3.26 g, 22.4 mmol) were added, and the mixture was stirred for 60hours. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 635 mg of compound 175B as a colorless solid.

Third Step

Compound 175B (632 mg, 1.22 mmol) and palladium-active carbon (10%, wet,100 mg) were added to ethanol (10 ml) and THF (5 ml), and the mixturewas stirred at room temperature for 3 hours under hydrogen atmosphere.After filtration with celite, the solvent was concentrated under reducedpressure to obtain 502 mg of a colorless oily substance 175C.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.77 (2H, m), 3.18-3.27 (1H, m),3.43-3.51 (1H, m), 4.04 (4H, m), 4.92 (1H, d, J=4.7 Hz), 7.28 (10H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390 mg, 1.22mmol) and compound 175C (468 mg, 1.22 mmol) were added to toluene (5ml), and the mixture was stirred at 100° C. for 2 hours. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography (n-hexane-ethylacetate, 1:1, v/v) to obtain 391 mg of compound 175D as a pale yellowgummy substance.

Fifth Step

To compound 175D (388 mg, 0.568 mmol) was added 4N HCl (ethyl acetatesolution, 4 ml). After the mixture was stirred at room temperature for 1hour, the solvent was distilled off under reduced pressure.Subsequently, toluene (4 ml) and 3-aminopropan-1-ol (0.0870 ml, 1.14mmol) were added, and the mixture was stirred at 80° C. for 5 hours.After the solvent was distilled off under reduced pressure, theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 98:2, v/v) to obtain 57 mg of compound 175E as ayellow gummy substance and 44 mg of compound 175F as a brown gummysubstance.

175E: ¹H-NMR (CDCl₃) δ: 1.91-2.00 (2H, m), 2.87 (1H, m), 3.78 (3H, s),3.87-4.15 (3H, m), 4.61 (1H, d, J=12.1 Hz), 4.78 (2H, m), 5.33 (1H, d,J=10.2 Hz), 5.63 (1H, d, J=10.2 Hz), 6.95 (2H, m), 7.13-7.53 (12H, m),7.76 (2H, m)

175F: ¹H-NMR (CDCl₃) δ: 1.83-1.97 (2H, m), 3.12-3.22 (1H, m), 3.50 (1H,m), 3.85 (3H, s), 3.90 (1H, m), 4.34-4.40 (1H, m), 4.74 (1H, d, J=8.6Hz), 4.84-4.89 (1H, m), 5.09 (1H, d, J=3.3 Hz), 5.15 (1H, d, J=9.9 Hz),5.26 (1H, d, J=9.6 Hz), 7.08-7.50 (13H, m), 7.65-7.77 (3H, m).

Sixth Step

Compound 175E (57 mg, 0.10 mmol) was dissolved in THF (0.5 ml) andethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml, 0.50mmol) was added at room temperature, and the mixture was stirred for 1hour. After 1N hydrochloric acid was added, and the mixture wasextracted with chloroform, the extract was dried with sodium sulfate.The solvent was distilled off under reduced pressure, the resultingcrude product was purified by silica gel column chromatography(chloroform-methanol, 98:2, v/v) to obtain compound 175G.

Seventh Step

To compound 175G obtained in the sixth step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, then the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 11 mg of compound 175 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.50 (1H, d, J=13.1 Hz), 1.79 (1H, m), 3.17 (1H, m),3.86 (1H, t, J=11.0 Hz), 4.03 (1H, dd, J=10.8, 4.1 Hz), 4.46 (1H, d,J=12.0 Hz), 4.53 (1H, dd, J=12.7, 4.2 Hz), 4.84 (1H, s), 5.85 (1H, d,J=11.7 Hz), 7.22 (7H, m), 7.44 (2H, t, J=7.6 Hz), 7.65 (2H, d, J=7.3Hz), 8.14 (1H, s), 12.75 (1H, s), 15.33 (1H, brs).

MS: m/z=447 [M+H]⁺.

Example 176

According to Example 175, using compound 175F, compound 176 wassynthesized by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.75 (2H, m), 3.17 (2H, m), 3.43 (1H, m), 3.60 (1H,d, J=10.7 Hz), 4.31 (1H, d, J=12.7 Hz), 4.73 (1H, d, J=9.8 Hz), 5.52(1H, d, J=3.4 Hz), 5.87 (1H, dd, J=9.9, 3.4 Hz), 7.10 (7H, m), 7.29 (2H,t, J=7.5 Hz), 7.58 (2H, d, J=7.3 Hz), 8.37 (1H, s), 12.65 (1H, brs).

MS: m/z=447 [M+H]⁺.

Example 177

First Step

Tert-butyl pyrazolidine-1-carboxylate (275 mg, 1.60 mmol) synthesizedaccording to the method of the reference (Journal of the ChemicalSociety, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1972-1999), 1975, p. 1712), and compound 95B (409 mg, 1.45 mmol) weredissolved in pyridine (5 ml), HATU (607 mg, 1.60 mmol) was added at roomtemperature, and the mixture was stirred for 18 hours. The reactionsolution was poured into 1N hydrochloric acid, then the mixture wasextracted with ethyl acetate, and the extract was dried with sodiumsulfate The solvent was distilled off under reduced pressure, and theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 97:3→95:5, v/v) to obtain 529 mg of compound 177Aas a yellow solid.

¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.88-2.10 (2H, m), 3.04 (1H, s), 3.31(1H, s), 3.86 (2H, m), 4.96 (1H, d, J=9.3 Hz), 5.45 (1H, d, J=11.0 Hz),6.56 (1H, d, J=6.7 Hz), 7.29-7.43 (6H, m).

Second Step

To compound 177A (525 mg, 1.31 mmol) was added 4N HCl (dioxane solution,6 ml). After the mixture was stirred at room temperature for 1.5 hours,the solvent was distilled off under reduced pressure to obtain 413 mg ofcompound 177B as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.95-2.05 (2H, m), 2.78 (2H, t, J=6.6 Hz), 3.41-3.54(2H, m), 5.11 (2H, s), 7.38 (5H, m), 7.46 (1H, d, J=6.6 Hz), 8.36 (1H,d, J=6.7 Hz).

Third Step

Compound 177B (100 mg, 0.298 mmol) was added to ethanol (2 ml),2,2-diphenylacetaldehyde (58 mg, 0.30 mmol), triethylamine (0.083 ml,0.596 mmol) and acetic acid (0.051 ml, 0.89 mmol) were added, and themixture was stirred at 80° C. for 3 hours. The reaction solution waspoured into water, the mixture was extracted with chloroform, and theextract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product was purified bysilica gel column chromatography (chloroform-methanol,97:3→95:5→93:7-90:10, v/v) to obtain 106 mg of compound 177C as a yellowgummy substance.

MS: m/z=478 [M+H]⁺.

Fourth Step

To compound 177C obtained in the third step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 7 mg of compound 177 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.95 (2H, m), 2.76 (1H, m), 2.96-3.17 (2H, m), 4.04(1H, m), 4.68 (1H, d, J=10.4 Hz), 5.66 (1H, d, J=7.3 Hz), 6.56 (1H, d,J=10.5 Hz), 7.03 (1H, d, J=7.2 Hz), 7.17 (6H, m), 7.34 (2H, t, J=7.3Hz), 7.55 (2H, d, J=7.5 Hz).

MS: m/z=388 [M+H]⁺.

Example 178

According to Example 177, compound 178 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.55 (4H, m), 2.35-7.49 (1H, m), 2.39 (1H, t, J=12.6Hz), 2.77 (1H, t, J=10.0 Hz), 3.09 (1H, d, J=11.4 Hz), 4.34 (1H, d,J=12.8 Hz), 4.55 (1H, d, J=10.8 Hz), 5.71 (1H, d, J=7.0 Hz), 6.17 (1H,d, J=10.8 Hz), 6.82 (1H, d, J=7.3 Hz), 7.13-7.40 (8H, m), 7.48 (2H, d,J=7.3 Hz).

MS: m/z=402 [M+H]⁺.

Example 179

According to Example 177, compound 179 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, m), 2.68 (2H, m), 3.21 (1H, m), 4.04 (1H,m), 4.40 (1H, d, J=10.8 Hz), 5.77 (1H, t, J=5.2 Hz), 6.26 (1H, d, J=10.8Hz), 6.78 (1H, d, J=7.3 Hz), 7.27 (8H, m), 7.53 (2H, d, J=7.2 Hz).

MS: m/z=416 [M+H]⁺.

Example 180

According to Example 177, compound 180 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.78-3.74 (7H, m), 4.17 (1H, m), 4.49 (1H, d, J=10.8Hz), 5.79 (1H, d, J=7.2 Hz), 6.32 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=7.2Hz), 7.28 (8H, m), 7.55 (2H, d, J=7.6 Hz).

MS: m/z=418 [M+H]⁺.

Using amines which are commercially available or known in the referencesand halides which are commercially available or known in the references,and according to the method of Example 12, Examples 181 to 187 weresynthesized.

Example 181

MS: m/z=433 [M+H]⁺.

Example 182

MS: m/z=459 [M+H]⁺.

Example 183

MS: m/z=529 [M+H]⁺.

Example 184

MS: m/z=477 [M+H]⁺.

Example 185

MS: m/z=473 [M+H]⁺.

Example 186

MS: m/z=447 [M+H]⁺.

Example 187

MS: m/z=461 [M+H]⁺

Example 188

According to Example 12 and Example 129, compound 188 was synthesized bythe same procedure.

MS: m/z=449 [M+H]⁺.

Using amines which are commercially available or known in the referencesand halides which are commercially available or known in the references,and according to the method of Example 95, Examples 189 to 229 weresynthesized.

Example 189

MS: m/z=399 [M+H]⁺.

Example 190

MS: m/z=488 [M+H]⁺

Example 191

MS: m/z=470 [M+H]⁺

Example 192

MS: m/z=422 [M+H]⁺.

Example 193

MS: m/z=422 [M+H]⁺

Example 194

MS: m/z=486 [M+H]⁺

Example 195

MS: m/z=365 [M+H]⁺

Example 196

MS: m/z=418 [M+H]⁺

Example 197

MS: m/z=339 [M+H]⁺

Example 198

MS: m/z=344 [M+H]⁺

Example 199

MS: m/z=383 [M+H]⁺

Example 200

MS: m/z=339 [M+H]⁺

Example 201

MS: m/z=440 [M+H]⁺

Example 202

MS: m/z=365 [M+H]⁺

Example 203

MS: m/z=396 [M+H]⁺

Example 204

MS: m/z=370 [M+H]⁺

Example 205

MS: m/z=390 [M+H]⁺

Example 206

MS: m/z=420 [M+H]⁺

Example 207

MS: m/z=350 [M+H]⁺

Example 208

MS: m/z=428 [M+H]⁺

Example 209

MS: m/z=386 [M+H]⁺

Example 210

MS: m/z=378 [M+H]⁺

Example 211

MS: m/z=366 [M+H]⁺

Example 212

MS: m/z=362 [M+H]⁺

Example 213

MS: m/z=358 [M+H]⁺

Example 214

MS: m/z=350 [M+H]⁺

Example 215

MS: m/z=350 [M+H]⁺

Example 216

MS: m/z=411 [M+H]⁺

Example 217

MS: m/z=445 [M+H]⁺

Example 218

MS: m/z=366 [M+H]⁺

Example 219

MS: m/z=354 [M+H]⁺

Example 220

MS: m/z=368 [M+H]⁺

Example 221

MS: m/z=314 [M+H]⁺

Example 222

MS: m/z=330 [M+H]⁺

Example 223

MS: m/z=346 [M+H]⁺

Example 224

MS: m/z=418 [M+H]⁺.

Example 225

MS: m/z=445 [M+H]⁺.

Example 226

MS: m/z=473 [M+H]⁺.

Example 227

MS: m/z=444 [M+H]⁺.

Example 228

MS: m/z=434 [M+H]⁺.

Example 229

MS: m/z=443 [M+H]⁺.

Example 230

According to Example 128, compound 230 was synthesized by the sameprocedure.

MS: m/z=461 [M+H]⁺.

Example 231

According to Example 129, compound 231 was synthesized by the sameprocedure.

MS: m/z=420 [M+H]⁺.

Example 232

According to Example 129, compound 232 was synthesized by the sameprocedure.

MS: m/z=434 [M+H]⁺.

Example 233

According to Example 130, compound 233 was synthesized by the sameprocedure.

MS: m/z=433 [M+H]⁺.

Example 234

According to Example 130, compound 234 was synthesized by the sameprocedure.

MS: m/z=447 [M+H]⁺.

Example 235

According to Example 130, compound 235 was synthesized by the sameprocedure

MS: m/z=473 [M+H]⁺.

Example 236

According to Example 130, compound 236 was synthesized by the sameprocedure.

MS: m/z=447 [M+H]⁺.

Example 237

According to Example 130, compound 237 was synthesized by the sameprocedure.

MS: m/z=487 [M+H]⁺.

Example 238

According to Example 130, compound 238 was synthesized by the sameprocedure.

MS: m/z=509 [M+H]⁺.

Example 239

MS: m/z=376 [M+H]⁺.

According to Example 157, compound 239 was synthesized by the sameprocedure.

Using amines which are commercially available or known in the referencesand alcohols which are commercially available or known in thereferences, and according to the method of Example 107, Examples 240 to245 were synthesized.

Example 240

¹H-NMR (CDCl₃) δ: 1.05 (3H, d, J=6.9 Hz), 1.04-1.14 (4H, m), 4.49 (1H,d, J=13.2 Hz), 4.83 (1H, d, J=13.2 Hz), 4.91-4.99 (1H, m), 5.73 (1H, d,J=7.8 Hz), 6.50 (1H, s), 6.70 (1H, d, J=7.8 Hz), 7.12-7.30 (4H, m),7.33-7.43 (2H, m), 7.46-7.54 (1H, m), 8.06 (1H, d, J=7.5 Hz).

Example 241

MS: m/z=478 [M+H]⁺.

Example 242

MS: m/z=478 [M+H]⁺.

Example 243

MS: m/z=478 [M+H]⁺.

Example 244

¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J=6.9 Hz), 4.59 (1H, d, J=12.6 Hz), 4.77(1H, d, J=12.6 Hz), 4.81-4.91 (1H, m), 5.82 (1H, d, J=7.5 Hz), 5.82 (1H,s), 6.71 (1H, brs), 6.78 (1H, brs), 6.87 (1H, d, J=7.5 Hz), 7.05 (1H,brs), 7.16 (1H, brs), 7.25 (1H, brs), 7.41 (1H, brs).

Example 245

MS: m/z=490 [M+H]⁺.

Example 246

First Step

To a dimethylformamide (20 ml) solution of compound 246A (5.30 g, 18.76mmol) and potassium carbonate (5.19 g, 27.53 mmol) was added benzylbromide (3.21 g, 18.76 mmol), and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added ethyl acetate(80 ml), insolubles were filtered off, and 1N hydrochloric acid wasadded. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate two times. The combined organic layers werewashed with water once and, further, washed with sodium bicarbonatewater once, and with an aqueous saturated sodium chloride solution once.The resulting solution was dried with sodium sulfate, and the solventwas distilled off to obtain 6.98 g of compound 246B as an oil.

¹H-NMR (CDCl₃) δ: 5.36 (2H, s), 7.35-7.47 (6H, m), 7.78 (1H, d, J=8.4Hz), 8.01 (1H, d, J=2.1 Hz).

Second Step

To a dimethylformamide (15 ml) solution of compound 246B (3 g, 8.05mmol) and 1-chloro-3-ethynylbenzene (1.32 g, 9.66 mmol) andtriethylamine (4.07 g, 40.25 mmol) were added copper chloride (76.6 mg,0.403 mmol) and dichlorobis(triphenylphosphine)palladium (282.5 mg,0.403 mmol) under nitrogen atmosphere, and the mixture was stirred atroom temperature for 5 hours. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Thecombined extracts were washed with water three times, and dried withsodium sulfate, then the solvent was distilled off. The resulting oilwas purified by silica gel column chromatography. The material wereeluted firstly with hexane and, then, with hexane-ethyl acetate (7:3,v/v). Concentration of an objective fraction afforded 3.10 g of compound246C as an oil.

¹H-NMR (CDCl₃) δ: 5.39 (2H, s), 7.21-7.46 (9H, m), 7.62 (1H, d, J=2.1Hz), 7.98 (1H, d, J=8.4 Hz).

Third Step

To a methanol (30 ml) solution of compound 246C (3.10 g, 8.05 mmol) wasadded 10% palladium carbon (620 mg, 20 wt %), and the mixture wasstirred at room temperature under 1 atm hydrogen atmosphere. Thereaction solution was filtered with celite, the solvent was distilledoff, to the resulting crude product were added ethyl acetate-diisopropylether, and the precipitated residue was filtered to obtain 618 mg ofcompound 246D as a solid.

¹H-NMR (CDCl₃) δ: 2.90 (2H, dd, J=7.8 Hz, 10.8 Hz), 3.29 (2H, dd, J=7.5Hz, 10.5 Hz), 7.06-7.09 (1H, m), 7.18-7.25 (4H, m), 7.31 (1H, dd, J=2.1Hz, 8.7 Hz), 8.05 (1H, d, J=8.4 Hz).

Fourth Step

To compound 246D (2.20 g, 7.45 mmol) was added polyphosphoric acid (20g), and the mixture was stirred at 200° C. for 1 hour. After cooled toroom temperature, water was added, and the mixture was extracted withethyl acetate three times. The combined extracts were washed withsaturated sodium bicarbonate water, and dried with sodium sulfate and,thereafter, the solvent was distilled off. The resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with hexane and, then, with hexane-ethyl acetate (7:3, v/v).Concentration of an objective fraction afforded 1.05 g of compound 246Eas an oil.

¹H-NMR (CDCl₃) δ: 3.17 (4H, s), 7.24 (2H, d, J=2.1 Hz), 7.32 (2H, dd,J=2.1 Hz, 8.4 Hz, 8.00 (2H, d, J=8.4 Hz).

Fifth Step

A methanol (10 ml) suspension of sodium borohydride (409 mg, 10.82 mmol)was cooled to 1 to 3° C., and compound 246E (1.0 g, 3.61 mmol) was addedwhile the same temperature was retained. After the reaction solution wasstirred at the same temperature for 30 minutes, water was added. Theprecipitated solid was filtered to obtain 968 mg of compound 246F.

¹H-NMR (CDCl₃) δ: 2.25 (1H, d, J=3.0 Hz), 3.05-3.16 (2H, m), 3.27-3.38(2H, m), 5.95 (1H, d, J=3.0 Hz), 7.14-7.17 (4H, m), 7.39 (2H, d, J=8.1Hz).

Sixth Step

According to Example 107, compound 246 was synthesized by the sameprocedure.

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.79(1H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz), 2.99-3.11 (1H, m), 3.50 (1H, ddd,J=4.8 Hz, 4.8 Hz), 17.7 Hz), 4.21-4.33 (1H, m), 4.23 (1H, d, J=12.9 Hz),4.62-4.74 (2H, m), 5.04 (1H, s), 5.84 (1H, d, J=7.8 Hz), 6.57 (1H, d,J=8.1 Hz), 6.65-6.72 (2H, m), 6.89-6.92 (1H, m), 7.11-7.30 (4H, m).

Using amines which are commercially available or known in the referencesand intermediates corresponding to compound 246A to compound 246F whichare commercially available or known in the references, and according tothe method of Example 246, compounds 247 to 284 were synthesized.

Example 247

MS: m/z=457 [M+H]⁺.

Example 248

MS: m/z=485 [M+H]⁺.

Example 249

MS: m/z=471 [M+H]⁺.

Example 250

MS: m/z=457 [M+H]⁺.

Example 251

MS: m/z=521 [M+H]⁺.

Example 252

MS: m/z=485 [M+H]⁺.

Example 253

MS: m/z=471 [M+H]⁺.

Example 254

MS: m/z=487 [M+H]⁺.

Example 255

MS: m/z=469 [M+H]⁺.

Example 256

MS: m/z=470 [M+H]⁺.

Example 257

MS: m/z=434 [M+H]⁺.

Example 258

¹H-NMR (DMSO-d₆) δ: 2.88 (3H, m), 3.43 (2H, m), 3.69 (1H, dt, J=16.9,5.1 Hz), 4.01 (1H, d, J=13.4 Hz), 4.07-4.17 (2H, m), 4.97 (1H, d, J=13.4Hz), 5.24 (1H, s), 5.50 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.2 Hz),6.85-6.94 (2H, m), 7.14-7.41 (6H, m), 11.73 (1H, s).

MS: m/z=432 [M+H]⁺.

Example 259

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, td, J=9.6, 4.5 Hz), 2.86-2.99 (1H, m),3.00-3.18 (1H, m), 3.67 (1H, dt, J=17.1, 5.0 Hz), 4.03-4.19 (2H, m),4.32-4.52 (1H, m), 5.05 (1H, d, J=13.3 Hz), 5.26 (1H, s), 5.53 (1H, d,J=7.6 Hz), 6.17 (1H, tt, J=55.0, 3.5 Hz), 6.72 (1H, d, J=7.5 Hz),6.87-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).

MS: m/z=438 [M+H]⁺.

Example 260

MS: m/z=460 [M+H]⁺.

Example 261

MS: m/z=474 [M+H]⁺.

Example 262

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, dt, J=14.2, 5.1 Hz), 2.86-2.99 (1H, m),3.00-3.18 (1H, m), 3.68 (1H, dt, J=16.9, 5.3 Hz), 4.05 (1H, d, J=13.3Hz), 4.07-4.32 (2H, m), 4.37-4.52 (1H, m), 4.53-4.67 (1H, m), 5.02 (1H,d, J=13.0 Hz), 5.26 (1H, s), 5.50 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.6Hz), 6.85-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).

MS: m/z=420 [M+H]⁺.

Example 263

¹H-NMR (DMSO-d₆) δ: 2.76-3.00 (2H, m), 3.46-3.73 (2H, m), 4.06-4.22 (2H,m), 4.77-4.91 (1H, m), 5.15 (1H, d, J=12.9 Hz), 5.24 (1H, s), 5.56 (1H,d, J=7.7 Hz), 6.72 (1H, d, J=7.1 Hz), 6.88-6.95 (1H, m), 6.96 (1H, d,J=7.7 Hz), 7.09-7.41 (7H, m).

MS: m/z=456 [M+H]⁺.

Example 264

¹H-NMR (DMSO-d₆) δ: 2.74-2.99 (2H, m), 3.62-3.73 (1H, m), 4.01-4.20 (3H,m), 5.12 (1H, d, J=13.2 Hz), 5.15 (1H, d, J=15.7 Hz), 5.34 (1H, s), 5.52(1H, d, J=7.7 Hz), 6.78 (1H, d, J=8.0 Hz), 6.89-6.96 (2H, m), 7.10-7.23(5H, m), 7.27-7.35 (3H, m), 7.43 (1H, d, J=7.7 Hz), 7.79 (1H, td, J=7.6,1.8 Hz), 8.45-8.50 (1H, m).

MS: m/z=465 [M+H]⁺.

Example 265

¹H-NMR (DMSO-d₆) δ: 1.32 (9H, s), 2.76-2.86 (1H, m), 2.87-3.01 (1H, m),3.59-3.70 (1H, m), 4.12-4.25 (1H, m), 4.29 (1H, d, J=13.5 Hz), 4.90 (1H,d, J=13.2 Hz), 5.20 (1H, s), 5.49 (1H, d, J=7.4 Hz), 6.75 (1H, d, J=8.0Hz), 6.81 (1H, d, J=7.4 Hz), 6.91 (1H, t, J=6.6 Hz), 7.12-7.21 (2H, m),7.22-7.30 (1H, m), 7.33-7.38 (2H, m), 7.46 (1H, d, J=7.4 Hz).

MS: m/z=430 [M+H]⁺.

Example 266

¹H-NMR (DMSO-d₆) δ: 1.05 (3H, t, J=7.2 Hz), 2.80 (1H, dt, J=14.4, 5.1Hz), 2.85-2.99 (2H, m), 3.68 (1H, dt, J=16.8, 5.0 Hz), 3.74-3.87 (1H,m), 4.02 (1H, d, J=13.3 Hz), 4.06-4.19 (1H, m), 4.98 (1H, d, J=13.1 Hz),5.22 (1H, s), 5.48 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83-6.94(2H, m), 7.12-7.40 (6H, m).

MS: m/z=402 [M+H]⁺.

Example 267

¹H-NMR (CDCl₃) δ: 1.74-1.86 (2H, m), 2.71-2.82 (1H, m), 2.83-2.93 (1H,m), 2.98-3.11 (1H, m), 3.25 (3H, s), 3.39 (2H, t, J=5.4 Hz), 3.62-3.74(1H, m), 4.02-4.14 (2H, m), 4.16-4.28 (1H, m), 4.82 (1H, d, J=13.2 Hz),5.03 (1H, s), 5.76 (1H, d, J=7.7 Hz), 6.58 (1H, d, J=7.7 Hz), 6.64 (1H,d, J=7.4 Hz), 6.89-6.97 (1H, m), 7.12-7.39 (6H, m).

MS: m/z=446 [M+H]⁺.

Example 268

¹H-NMR (CDCl₃) δ: 1.09 (3H, t, J=7.0 Hz), 2.65-2.77 (1H, m), 2.83-2.94(1H, m), 2.97-3.10 (1H, m), 3.40 (2H, q, J=7.0 Hz), 3.45-3.52 (1H, m),3.55-3.64 (1H, m), 3.65-3.76 (1H, m), 4.00-4.15 (2H, m), 4.36-4.45 (1H,m), 4.90 (1H, d, J=13.5 Hz), 5.02 (1H, s), 5.79 (1H, d, J=7.7 Hz), 6.59(1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.4 Hz), 6.90-6.97 (1H, m), 7.13-7.39(6H, m).

MS: m/z=446 [M+H]⁺.

Example 269

MS: m/z=480 [M+H]⁺.

Example 270

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.85 (2H, m), 3.68 (1H, m), 4.16 (1H,m), 4.29 (1H, d, J=13.3 Hz), 4.45 (1H, d, J=17.1 Hz), 5.12 (1H, d,J=13.1 Hz), 5.26 (1H, d, J=17.4 Hz), 5.36 (1H, s), 5.55 (1H, d, J=7.6Hz), 6.74 (1H, d, J=7.6 Hz), 6.89-7.38 (8H, m).

MS: m/z=470 [M+H]⁺.

Example 271

¹H-NMR (DMSO-d₆) δ: 2.87 (2H, m), 3.61-3.69 (1H, m), 4.15 (1H, m), 4.18(1H, d, J=13.2 Hz), 4.51 (1H, d, J=15.9 Hz), 5.08 (1H, d, J=13.1 Hz),5.21 (1H, s), 5.22 (1H, d, J=15.6 Hz), 5.52 (1H, d, J=7.6 Hz), 6.72 (1H,d, J=7.5 Hz), 6.89-7.32 (8H, m), 7.76 (2H, s).

MS: m/z=471 [M+H]⁺.

Example 272

MS: m/z=476 [M+H]⁺.

Example 273

¹H-NMR (CDCl₃) δ: 2.84-2.93 (1H, m), 2.98 (3H, s), 2.98-3.09 (1H, m),3.66-3.75 (1H, m), 3.99-4.15 (1H, m), 4.06 (1H, d, J=12.9 Hz), 4.80 (1H,d, J=13.2 Hz), 5.03 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.5Hz), 6.63 (1H, d, J=6.6 Hz), 6.90-6.96 (1H, m), 7.14-7.37 (6H, m).

Example 274

MS: m/z=470 [M+H]⁺.

Example 275

MS: m/z=470 [M+H]⁺

Example 276

MS: m/z=460 [M+H]⁺

Example 277

MS: m/z=486 [M+H]⁺.

Example 278

MS: m/z=446 [M+H]⁺

Example 279

¹H-NMR (CDCl₃) δ: 1.08-1.21 (6H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz,14.4 Hz), 2.97-3.08 (1H, m), 3.54 (1H, ddd, J=4.8 Hz, 6.6 Hz, 17.1 Hz),4.09-4.26 (1H, m), 4.24 (1H, d, J=13.2 Hz), 4.64-4.74 (m, 1H), 4.70 (1H,d, J=13.2 Hz), 4.94 (1H, s), 5.81 (1H, d, J=7.8 Hz), 6.42 (1H, dd, J=2.7Hz, 9.0 Hz), 6.67 (1H, d, J=7.8 Hz), 6.89-7.12 (4H, m), 7.19-7.36 (1H,m).

Example 280

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.84(1H, ddd, J=4.8 Hz, 5.1 Hz, 14.4 Hz), 2.96-3.07 (1H, m), 3.55 (1H, ddd,J=4.8 Hz, 5.1 Hz, 17.4 Hz), 4.11-4.23 (1H, m), 4.21 (1H, d, J=12.9 Hz),4.65-4.74 (1H, m), 4.70 (1H, d, J=12.9 Hz), 4.95 (1H, s), 5.78 (1H, d,J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=2.1 Hz), 7.06 (1H, d,J=8.4 Hz), 7.18 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.23-7.26 (2H, m), 7.24 (1H,dd, J=2.1 Hz, 8.1 Hz).

Example 281

¹H-NMR (C-DCl₃) δ: 1.13 (3H, d, J=6.6 Hz), 1.20 (3H, d, J=6.9 Hz),2.90-3.32 (1H, m), 3.36 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.6 Hz), 3.42-3.51(1H, m), 3.95-4.02 (1H, m), 4.28 (1H, d, J=12.9 Hz), 4.64-4.75 (1H, m),1.89 (1H, d, J=12.9 Hz), 5.15 (1H, s), 5.80 (1H, d, J=7.5 Hz), 6.46-6.49(1H, m), 6.70 (1H, d, J=7.8 Hz), 6.88-7.00 (2H, m), 7.03-7.06 (1H, m),7.11-7.22 (2H, m).

Example 282

¹H-NMR (CDCl₃) δ: 1.09-1.19 (6H, m), 2.80-3.10 (2H, m), 3.40-3.60 (1H,m), 4.16-4.41 (2H, m), 4.61-4.47 (2H, m), 5.06-5.10 (1H, m), 5.71(0.45H, d, J=7.5 Hz), 5.74 (0.55H, d, J=7.8 Hz), 6.60-6.72 (2H, m),6.86-6.94 (1H, m), 7.10-7.46 (6H, m).

Example 283

¹H-NMR (CDCl₃) δ: 1.10-1.21 (6H, m), 2.75-2, 86 (1H, m), 2.99-3.14 (1H,m), 4.23-4.37 (2H, m), 4, 59-4.74 (2H, m), 5.04 (1H, s), 5.67-5.80 (1H,m), 6.58-6.67 (2H, m), 6.88-7.08 (1H, m), 7.11-7.38 (5H, m).

Example 284

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 9.9 Hz), 3.07 (1H, t, J=3.9 Hz, 13.2 Hz,13.2 Hz), 3.50 (1H, ddd, J=4.2 Hz, 4.2 Hz, 18.0 Hz), 4.24 (1H, 6.9 Hz),4.34 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.63-4.74 (2H, m), 5.06 (1H,s), 5.81 (1H, d, J=7.8 Hz), 6.57-6.64 (2H, m), 6.65 (1H, d, J=7.5 Hz),6.82 (1H, d, J=9.3 Hz), 6.90 (1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.02(1H, dd, J=2.7 Hz, 9.0 Hz), 7.19-7.26 (2H, m).

Example 285

First Step

Compound 285A (5.00 g, 29.3 mmol) was dissolved in dimethylformamide(150 ml), potassium carbonate (14.2 mmol) and iodoethane (7.11 ml, 88.0mmol) were added, and the mixture was stirred at room temperature for 2hours. To the reaction solution was added hexane, and the mixture waswashed with water and an aqueous saturated sodium chloride solution. Theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a colorless oilysubstance 285B.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 2.60 (3H, s), 4.37 (2H, q,J=7.1 Hz), 7.17 (1H, td, J=7.9, 0.6 Hz), 7.49 (1H, ddd, J=8.0, 1.4, 0.4Hz), 7.68 (1H, ddd, J=7.8, 1.4, 0.3 Hz).

Second Step

Compound 285B (5.63 g, 28.3 mmol) obtained in the first step wasdissolved in carbon tetrachloride (150 ml), N-bromosuccinimide (5.55 g,31.2 mmol) was added, and the mixture was stirred at 100° C. for 18hours. The reaction solution was cooled to room temperature, and washedwith water and an aqueous saturated sodium chloride solution. Theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 8.08 g of an orange oilysubstance 285C.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.6 Hz), 4.42 (2H, q, J=7.1 Hz), 5.10(2H, s), 7.31 (1H, t, J=8.6 Hz), 7.57 (1H, d, J=8.1 Hz), 7.84 (1H, d,J=8.1 Hz).

Third Step

Compound 285C (2.17 g, 7.8 mmol) obtained in the second step wasdissolved in acetone (25 ml), 4-fluorobenzenethiol (1.00 g, 7.80 mmol)and potassium carbonate (1.62 g, 11.7 mmol) were added, and the mixturewas stirred at 80° C. for 18 hours. After cooled to room temperature,the reaction solution was poured into water, the mixture was extractedwith ethyl acetate, the extract was washed with an aqueous saturatedsodium chloride solution, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting crude product was purified by silica gel column chromatographyand eluted with n-hexane-ethyl acetate (4:1, v/v) to obtain 2.20 g of acolorless oily substance 285D.

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 4.25 (2H, d, J=7.5 Hz), 4.65(2H, s), 6.91 (2H, t, J=8.8 Hz), 7.19-7.31 (3H, m), 7.48 (1H, dd, J=8.2,1.4 Hz), 7.70 (1H, dd, J=7.6, 1.5 Hz).

Fourth Step

Compound 285D (2.20 g, 6.77 mmol) obtained in the third step wasdissolved in ethanol (20 ml), a 2N aqueous sodium hydroxide solution(16.9 ml, 33.8 mmol) was added, and the mixture was stirred at roomtemperature for 3 hours. To the reaction solution was added water, themixture was made acidic with dilute hydrochloric acid, and extractedwith ethyl acetate. The organic layer was washed with an aqueoussaturated sodium chloride solution, and dried with sodium sulfate, andthe solvent was distilled off under reduced pressure. To the resultingcompound was added n-hexane, and the precipitated residue was filteredto obtain 1.81 g of a white solid 285E.

¹H-NMR (CDCl₃) δ: 4.74 (2H, s), 6.95 (2H, t, J=8.8 Hz), 7.34 (3H, m),7.59 (1H, dd, J=7.9, 1.5 Hz), 7.92 (1H, dd, J=7.9, 1.3 Hz).

Fifth Step

To compound 285E (1.81 g, 6.10 mmol) obtained in the fourth step wasadded polyphosphoric acid (10.0 g), and the mixture was stirred at 120°C. for 5 hours. After cooled to room temperature, water was added, andthe mixture was extracted with ethyl acetate. The organic layer wasdried with sodium sulfate, the solvent was concentrated under reducedpressure, to the resulting compound were added n-hexane-ethyl acetate,and the precipitated residue was filtered to obtain 1.18 g of a whitesolid 285F.

¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 7.18 (1H, ddd, J=9.3, 6.6, 2.3 Hz), 7.33(2H, m), 7.46 (1H, dd, J=7.7, 1.5 Hz), 7.59 (1H, dd, J=7.9, 1.3 Hz),7.91 (1H, dd, J=10.1, 2.9 Hz).

Sixth Step

To compound 285F (1.17 g, 4.20 mmol) was added methanol (15 ml), sodiumborohydride (191 mg, 5.04 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 2 hours. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 945 mg of a white solid 285G.

¹H-NMR (CDCl₃) δ: 2.58 (1H, d, J=3.2 Hz), 4.46 (1H, d, J=14.3 Hz), 4.58(1H, d, J=14.6 Hz), 6.33 (1H, d, J=3.7 Hz), 6.82 (1H, td, J=8.3, 2.9Hz), 7.07 (1H, dd, J=8.5, 5.4 Hz), 7.20 (1H, t, J=7.9 Hz), 7.33 (2H, m),7.44 (1H, d, J=6.9 Hz).

Seventh Step

According to the same procedure as that of Example 107, compound 285 wassynthesized.

MS: m/z=486 [M+H]⁺.

Using amines which are commercially available or known in the referencesand intermediates corresponding to compound 285A to compound 285G whichare commercially available or known in the references. Then according tothe method of Example 285, compounds 286 to compound 359 weresynthesized.

Example 286

MS: m/z=595 [M+H]⁺.

Example 287

MS: m/z=475 [M+H]⁺.

Example 288

¹H-NMR (DMSO-d₆) δ: 1.57 (1H, brs), 1.84-1.99 (2H, m), 2.68 (3H, d,J=4.6 Hz), 3.08-3.17 (2H, m), 3.39 (3H, brs), 3.89 (1H, d, J=13.4 Hz),4.16 (1H, d, J=13.3 Hz), 4.54 (1H, brs), 5.10 (1H, d, J=12.7 Hz), 5.50(1H, s), 5.63 (1H, d, J=13.4 Hz), 5.73 (1H, d, J=7.8 Hz), 6.82-7.94 (9H,m).

MS: m/z=489 [M+H]⁺.

Example 289

MS: m/z=503 [M+H]⁺.

Example 290

MS: m/z=505 [M+H]⁺.

Example 291

MS: m/z=517 [M+H]⁺.

Example 292

MS: m/z=503 [M+H]⁺.

Example 293

MS: m/z=489 [M+H]⁺.

Example 294

MS: m/z=456 [M+H]⁺.

Example 295

MS: m/z=488 [M+H]⁺.

Example 296

MS: m/z=498 [M+H]⁺.

Example 297

¹H-NMR (DMSO-d₆) δ: 3.21 (1H, m), 3.85 (1H, d, J=13.4 Hz), 4.08-4.18(3H, m), 4.28 (1H, d, J=13.4 Hz), 5.10 (1H, d, J=13.7 Hz), 5.45 (1H, s),5.57-5.64 (2H, m), 6.82-7.50 (10H, m).

MS: m/z=504 [M+H]⁺.

Example 298

According to Example 107, compound 298 was synthesized by the sameprocedure.

MS: m/z=452 [M+H]⁺.

Example 299

MS: m/z=450 [M+H]⁺.

Example 300

MS: m/z=464 [M+H]⁺.

Example 301

¹H-NMR (DMSO-d₆) δ: 1.00 (3H, d, J=6.9 Hz), 1.06 (3H, d, J=6.9 Hz), 3.88(1H, d, J=13.4 Hz), 4.32 (1H, d, J=13.3 Hz), 4.67 (1H, m), 4.97 (1H, d,J=13.4 Hz), 5.43 (1H, s), 5.59 (2H, m), 6.84-7.45 (9H, m), 11.90 (1H,brs).

MS: m/z=434 [M+H]⁺.

Example 302

¹H-NMR (DMSO-d₆) δ: 0.11 (1H, m), 0.54-0.92 (3H, m), 2.71 (1H, m), 3.85(1H, d, J=13.7 Hz), 4.06 (1H, d, J=13.1 Hz), 5.06 (1H, d, J=13.1 Hz),5.35 (1H, s), 5.57 (2H, m), 7.15 (9H, m), 11.66 (1H, brs).

MS: m/z=432 [M+H]⁺.

Example 303

¹HNMR (CDCl₃) δ: 1.14 (1H, m), 1.54 (2H, m), 1.67 (1H, m), 3.60 (1H, d,J=13.5 Hz), 4.39 (1H, d, J=12.6 Hz), 5.02 (1H, s), 5.07 (1H, d, J=12.6Hz), 5.60 (1H, d. J=13.5 Hz), 5.77 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7Hz), 7.07-7.13 (3H, m), 7.25-7.44 (4H, m).

MS: m/z=457.10 [M+H]⁺.

Example 304

¹H-NMR (DMSO-d₆) δ: 3.33-3.42 (1H, m), 3.84 (1H, d, J=13.1 Hz),3.90-4.10 (1H, m), 4.24 (1H, d, J=13.4 Hz), 4.35-4.66 (2H, m), 5.13 (1H,d, J=13.4 Hz), 5.43 (1H, s), 5.54-5.64 (2H, m), 6.80-6.95 (2H, m),7.04-7.50 (8H, m).

MS: m/z=438 [M+H]⁺.

Example 305

MS: m/z=487 [M+H]⁺.

Example 306

¹H-NMR (DMSO-d₆) δ: 3.69-3.82 (1H, m), 3.89 (1H, d, J=13.6 Hz), 4.40(1H, d, J=12.9 Hz), 4.60-4.77 (1H, m), 5.27 (1H, d, J=13.3 Hz), 5.43(1H, s), 5.60 (1H, d, J=13.6 Hz), 5.70 (1H, d, J=7.7 Hz), 6.84-6.95 (1H,m), 7.08-7.55 (9H, m).

MS: m/z=474 [M+H]⁺.

Example 307

¹H-NMR (DMSO-d₆) δ: 3.81 (1H, d, J=13.5 Hz), 4.29 (1H, d, J=13.5 Hz),4.33 (1H, d, J=16.2 Hz), 4.96 (1H, d, J=16.2 Hz), 5.23 (1H, d, J=13.5Hz), 5.49 (1H, s), 5.59 (1H, d, J=13.2 Hz), 5.64 (1H, d, J=7.7 Hz),6.82-6.97 (2H, m), 7.05-7.41 (10H, m), 7.80 (1H, td, J=7.6, 1.7 Hz),8.47 (1H, d, J=4.9 Hz).

MS: m/z=483 [M+H]⁺.

Example 308

¹H-NMR (DMSO-d₆) δ: 1.28 (9H, s), 3.86 (1H, d, J=13.6 Hz), 4.42 (1H, d,J=13.3 Hz), 4.99 (1H, d, J=13.4 Hz), 5.32 (1H, s), 5.53 (1H, d, J=13.3Hz), 5.60 (1H, d, J=7.6 Hz), 6.81-7.63 (10H, m).

MS: m/z=448 [M+H]⁺.

Example 309

¹H-NMR (DMSO-d₆) δ: 1.03 (3H, t, J=7.4 Hz), 3.12-3.26 (1H, m), 3.43-3.58(1H, m), 3.85 (1H, d, J=13.6 Hz), 4.21 (1H, d, J=13.4 Hz), 5.07 (1H, d,J=13.4 Hz), 5.40 (1H, s), 5.57 (1H, d, J=13.1 Hz), 5.59 (1H, d, J=7.3Hz), 6.80-6.88 (1H, m), 6.91 (1H, d, J=7.9 Hz), 7.03-7.55 (8H, m).

MS: m/z=420 [M+H]⁺.

Example 310

MS: m/z=498 [M+H]⁺.

Example 311

¹H-NMR (CDCl₃) δ: 1.73-1.85 (2H, m), 2.96-3.07 (1H, m), 3.27 (3H, s),3.42 (2H, t, J=5.6 Hz), 3.56 (1H, d, J=13.5 Hz), 3.93-4.04 (1H, m), 4.25(1H, d, J=13.2 Hz), 4.95 (1H, d, J=12.9 Hz), 5.13 (1H, s), 5.65 (1H, d,J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 6.78-6.86(1H, m), 7.03-7.15 (3H, m), 7.17-7.47 (5H, m).

MS: m/z=464 [M+H]⁺.

Example 312

¹H-NMR (CDCl₃) δ: 1.10 (3H, t, J=6.9 Hz), 2.79-2.91 (1H, m), 3.41 (2H,q, J=7.1 Hz), 3.46-3.69 (3H, m), 4.30 (1H, d, J=13.5 Hz), 5.01 (1H, d,J=13.5 Hz), 5.12 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.83 (1H, d, J=7.7Hz), 6.68 (1H, d, J=7.7 Hz), 6.77-6.86 (1H, m), 7.03-7.12 (3H, m),7.16-7.46 (5H, m).

MS: m/z=464 [M+H]⁺.

Example 313

¹H-NMR (CDCl₃) δ: 1.30-1.47 (1H, m), 1.49-1.67 (1H, m), 1.73-2.02 (4H,m), 2.09-2.23 (2H, m), 3.60 (1H, d, J=13.5 Hz), 4.39 (1H, d, J=12.9 Hz),4.45-4.64 (1H, m), 4.93 (1H, d, J=12.6 Hz), 5.10 (1H, s), 5.65 (1H, d,J=13.5 Hz), 5.87 (1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.0 Hz), 6.76-6.85(1H, m), 7.08 (2H, d, J=3.8 Hz), 7.16 (2H, d, J=7.7 Hz), 7.23-7.31 (1H,m), 7.34-7.48 (2H, m).

MS: m/z=510 [M+H]⁺.

Example 314

MS: m/z=476 [M+H]⁺.

Example 315

MS: m/z=488 [M+H]⁺.

Example 316

¹H-NMR (DMSO-d₆) δ: 3.83 (1H, d, J=13.4 Hz), 4.34 (1H, d, J=13.1 Hz),4.67 (1H, d, J=15.9 Hz), 5.05 (1H, d, J=15.9 Hz), 5.20 (1H, d, J=13.4Hz), 5.33 (1H, s), 5.60 (1H, d, J=13.8 Hz), 5.64 (1H, d, J=7.8 Hz), 6.87(3H, m), 7.05-7.19 (4H, m), 7.35-7.44 (2H, m), 7.74 (1H, d, 3.3 Hz),7.77 (1H, d, 3.3 Hz).

Example 317

MS: m/z=464 [M+H]⁺.

Example 318

MS: m/z=494 [M+H]⁺.

Example 319

¹H-NMR (CDCl₃) δ: 3.18-3.35 (1H, m), 3.60 (1H, d, J=13.7 Hz), 4.37 (1H,d, J=13.2 Hz), 4.75-4.95 (1H, m), 5.07-5.15 (2H, m), 5.60 (1H, d, J=13.7Hz), 5.85 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.79-6.88 (1H, m),7.09-7.14 (3H, m), 7.16 (1H, d, J=7.7 Hz), 7.29-7.36 (1H, m), 7.36-7.41(1H, m), 7.42-7.50 (1H, m).

MS: m/z=524 [M+H]⁺.

Example 320

¹H-NMR (CDCl₃) δ: 0.89 (9H, s), 0.97 (3H, d, J=7.1 Hz), 3.61 (1H, d,J=13.2 Hz), 4.43 (1H, d, J=13.2 Hz), 4.84-4.92 (2H, m), 5.11 (1H, s),5.70 (1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=7.4 Hz),6.79-6.85 (1H, m), 7.03-7.09 (2H, m), 7.16-7.24 (3H, m), 7.29-7.44 (2H,m).

MS: m/z=476 [M+H]⁺.

Example 321

¹H-NMR (CDCl₃) δ: 2.87 (0.75H, s), 3.01 (2.25H, s), 3.55 (1.5H, d,J=10.2 Hz), 3.62 (0.5H, 13.5 Hz), 4.17 (0.5H, d, J=13.2 Hz), 4.22 (1.5Hz, J=12.9 Hz), 4.97 (1H, d, J=12.9 Hz), 5.02 (0.25H, s), 5.11 (0.75H,s), 5.63 (0.75H, d, J=13.5 Hz), 5.77-5.83 (1.25H, m), 6.64-6.68 (1H, m),6.76-6.85 (1H, m), 7.01 (1H, d, J=7.5 Hz), 7.05-7.13 (2H, m), 7.17-7.45(3H, m).

Example 322

¹H-NMR (CDCl₃) δ: 3.63 (1H, d, J=13.4 Hz), 4.51-4.59 (2H, m), 4.68-4.98(4H, m), 5.13 (1H, d, J=12.9 Hz), 5.28 (1H, s), 5.71 (1H, d, J=13.3 Hz),5.85 (1H, d, J=7.7 Hz), 6.77 (1H, d, J=7.4 Hz), 6.82-6.89 (1H, m), 7.12(2H, d, J=3.5 Hz), 7.24 (1H, d, J=7.6 Hz), 7.33 (2H, d, J=4.4 Hz), 7.39(1H, d, J=7.1 Hz), 7.42-7.50 (1H, m).

MS: m/z=470 [M+H]⁺.

Example 323

MS: m/z=450 [M+H]⁺.

Example 324

MS: m/z=482 [M+H]⁺.

Example 325

¹H-NMR (DMSO-d₆) δ: 1.93 (3H, s), 3.13 (1H, m), 3.86 (1H, d, J=13.6 Hz),4.06 (3H, m), 4.26 (1H, d, J=13.3 Hz), 5.14 (1H, d, J=13.6 Hz), 5.44(1H, s), 5.60 (2H, m), 6.82-7.49 (10H, m).

MS: m/z=478 [M+H]⁺.

Example 326

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.10 (3H, d, J=6.9 Hz), 3.70(1H, d, J=13.5 Hz), 4.37 (1H, d, J=12.9 Hz), 4.75-4.85 (2H, m), 5.18(1H, s), 5.76 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.67 (1H, dd,J=1.2 Hz, 7.8 Hz), 6.77 (1H, t, J=7.8 Hz), 7.07 (1H, d, J=7.5 Hz),7.18-7.30 (3H, m), 7.35-7.46 (2H, m).

Example 327

¹H-NMR (CDCl₃) δ: 1.06 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.2 Hz), 3.60(H, d, J=13.5 Hz), 4.36 (1H, d, J=12.9 Hz), 4.75-4.83 (2H, m), 5.10 (1H,s), 5.67 (1H, d, J=13.2 Hz), 5.86 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=8, 1Hz), 6.78 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.08-7.18 (2H, m), 7.13 (1H, d,J=8.1 Hz), 7.24-7.30 (1H, m), 7.33-7.36 (1H, m), 7.39-7.45 (1H, m).

Example 328

¹H-NMR (CDCl₃) δ: 0.98 (0.4H, d, J=7.2 Hz), 1.07 (2.6H, d, J=6.6 Hz),1.15 (2.6H, d, J=6.9 Hz), 1.27 (0.4H, d, J=0.6 Hz), 3.62 (0.9H, d,J=13.2 Hz), 3.73 (0.1H, d, J=13.8 Hz), 4.36 (1H, d, J=12.9 Hz),4.77-4.88 (1H, m), 4.83 (1H, d, J=12.9 Hz), 5.07 (1H, s), 5.62 (1H, d,J=13.2 Hz), 5.77 (0.1H, d, J=7.5 Hz), 5.85 (0.9H, d, J=7.8 Hz),6.69-6.83 (1H, m), 6.98-7.07 (2H, m), 7.18 (2H, d, J=7.8 Hz), 7.25-7.35(2H, m), 7.40-7.45 (1H, m).

Example 329

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.15 (3H, d, J=6.9 Hz), 3.63(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.77-4.8 (1H, m), 4.82 (1H,d, J=12.6 Hz), 5.06 (1H, s), 5.60 (1H, d, J=12.9 Hz), 5.85 (1H, d, J=7.8Hz), 6.53 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.80-6.86 (1H, m), 7.03 (1H, dd,J=4.2 Hz, 9.0 Hz), 7.16-7.30 (3H, m), 7.35 (1H, d, J=6.3 Hz), 7.40-7.45(1H, m).

Example 330

¹H-NMR (DMSO-d₆) δ: 1.02 (3H, t, J=7.2 Hz), 3.07-3.22 (1H, m), 3.44-3.59(1H, m), 4.00 (1H, d, J=13.4 Hz), 4.21 (1H, d, J=13.4 Hz), 5.06 (1H, d,J=13.3 Hz), 5.47-5.76 (3H, m), 6.84-6.92 (1H, m), 6.92-6.99 (1H, m),7.04 (1H, d, J=7.6 Hz), 7.10-7.52 (6H, m).

MS: m/z=454 [M+H]⁺.

Example 331

¹H-NMR (CDCl₃) δ: 2.96 (0.79H, s), 3.00 (2.2H, s), 3.59 (0.75H, d,J=13.2 Hz), 3.62 (0.25H, d, J=13.8 Hz), 4.15 (0.25H, d, J=13.2 Hz), 4.21(0.75H, d, J=12.9 Hz), 4.95-5.01 (2H, m), 5.07 (1H, s), 5.56 (1H, d,J=13.5 Hz), 5.75-5.79 (1H, m), 5.88 (1H, d, J=7.8 Hz), 6.63 (0.36H, d,J=7.8 Hz), 6.73 (1H, d, J=1.8 Hz), 6.83 (0.39H, d, J=7.2 Hz), 7.01-7.46(7.25H, m).

Example 332

MS: m/z=484 [M+H]⁺.

Example 333

MS: m/z=484 [M+H]⁺.

Example 334

¹H-NMR (DMSO-d₆) δ: 3.01-3.10 (1H, m), 3.16 (3H, s), 3.40 (2H, m), 3.89(2H, d, J=13.4 Hz), 4.19 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.6 Hz),5.49 (1H, s), 5.58 (1H, d, J=13.4 Hz), 5.70 (1H, d, J=7.8 Hz), 6.89-7.48(8H, m), 11.36 (1H, s).

Example 335

¹H-NMR (DMSO-d₆) δ: 3.00-3.09 (1H, m), 3.15 (3H, s), 3.39 (2H, m), 3.94(1H, m), 4.00 (1H, d, J=13.2 Hz), 4.20 (1H, d, J=13.4 Hz), 5.06 (1H, d,J=13.4 Hz), 5.54 (1H, s), 5.65 (2H, m), 6.86-7.50 (8H, m), 11.54 (1H,brs).

Example 336

¹H-NMR (DMSO-d₆) δ: 3.01-3.09 (1H, m), 3.15 (3H, s), 3.40 (2H, m),3.87-3.94 (1H, m), 3.98 (1H, d, J=13.6 Hz), 4.20 (1H, d, J=13.6 Hz),5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s), 5.62 (1H, d, J=13.6 Hz), 5.67(1H, d, J=7.6 Hz), 6.78-7.50 (8H, m).

MS: m/z=468 [M+H]⁺

Example 337

¹H-NMR (DMSO-d₆) δ: 3.07 (1H, m), 3.16 (3H, s), 3.41 (2H, s), 3.89 (1H,d, J=13.7 Hz), 3.91 (1H, m), 4.19 (1H, d, J=13.6 Hz), 5.06 (1H, d,J=13.6 Hz), 5.48 (1H, s), 5.61 (1H, d, J=13.3 Hz), 5.69 (1H, d, J=7.6Hz), 6.70-7.48 (9H, m).

MS: m/z=468 [M+H]⁺

Example 338

MS: m/z=468 [M+H]⁺

Example 339

¹H-NMR (DMSO-d₆) δ: 3.14 (3H, s), 3.18 (s, 3H), 3.50 (4H, m), 4.00 (1H,d, J=13.1 Hz), 4.49 (1H, d, J=13.3 Hz), 4.77 (1H, ml, 4.95 (1H, d,J=13.3 Hz), 5.56 (1H, s), 5.68 (2H, m), 7.14 (8H, m).

MS: m/z=512 [M+H]⁺

Example 340

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.20 (3H, s), 3.51 (4H, m), 3.96 (1H,d, J=13.3 Hz), 4.53 (1H, d, J=13.4 Hz), 4.75 (1H, m), 4.97 (1H, d,J=13.1 Hz), 5.50 (1H, d, J=13.3 Hz), 5.54 (1H, s), 5.67 (1H, d, J=7.8Hz), 6.87-7.54 (8H, m).

MS: m/z=530 [M+H]⁺

Example 341

MS: m/z=466 [M+H]⁺

Example 342

MS: m/z=506 [M+H]⁺

Example 343

MS: m/z=522 [M+H]⁺

Example 344

MS: m/z=506 [M+H]⁺

Example 345

MS: m/z=506 [M+H]⁺

Example 346

MS: m/z=470 [M+H]⁺

Example 347

¹H-NMR (CDCl₃) δ: 2.88 (0.60H, s), 2.99 (2.40H, s), 3.67 (0.80H, d,J=13.8 Hz), 3.73 (0.20H, d, J=14.1 Hz), 4.16 (0.20H, d, J=11.1 Hz), 4.20(0.80H, d, J=12.9 Hz), 4.97 (0.80H, d, J=12.9 Hz), 4.99 (0.20H, d, J=15Hz), 5.10 (0.20H, s), 5.18 (0.80H, s), 5.69 (0.80H, d, J=13.5 Hz), 5.79(0.20H, d, J=7.8 Hz), 5.85 (0.80H, d, J=7.5 Hz), 5.88 (0.20H, J=13.5Hz), 6.62-6.66 (1H, m), 6.75-6.85 (1H, m), 6.98 (1H, d, J=7.5 Hz),7.03-7.16 (0.5H, m), 7.19 (1H, d, J=6.9 Hz), 7.24-7.39 (2.5H, m),7.43-7.48 (1H, m).

Example 348

¹H-NMR (CDCl₃) δ: 2.91 (0.75H, s), 2.99 (2.25H, s), 3.57 (0.75H, d,J=13.8 Hz), 3.63 (0.25H, d, 13.8 Hz), 4.17 (0.25H, d, J=12.9 Hz), 4.10(0.75H, d, J=12.9 Hz), 4.99 (0.75H, d, J=12.9 Hz), 5.00 (0.25H, s), 5.01(0.25H, d, J=12.3 Hz), 5.10 (0.75H, s), 5.61 (0.75H, d, J=13.5 Hz), 5.78(0.25H, J=7.5 Hz), 5.80 (0.25H, J=15 Hz), 5.89 (0.75H, d, J=7.5 Hz),6.60 (0.75H, d, J=8.4 Hz), 6.64 (0.25H, d, J=7.8 Hz), 6.78 (1H, dd,J=2.1 Hz, 8.1 Hz), 7.03 (1H, d, J=7.8 Hz), 7.04-7.21 (2H, m), 7.26-7.36(2H, m), 7.41-7.47 (1H, m).

Example 349

¹H-NMR (CDCl₃) δ: 2.94 (0.66H, s), 3.00 (2.34H, s), 3.60 (0.78H, d,J=13.5 Hz), 3.65 (0.22H, d, J=3.8 Hz), 4.22 (1H, d, J=12.9 Hz),4.94-5.00 (1H, m), 5.06 (1H, s), 5.54 (0.78H, d, J=13.2 Hz), 5.71(0.22H, d, J=13.8 Hz), 5.78 (0.22H, d, J=7.5 Hz), 5.88 (0.78H, d, J=7.8Hz), 6.49 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.66 (0.22H, d, J=7.8 Hz),6.82-6.88 (1H, m), 6.97-7.13 (2H, m), 7.16-7.21 (1H, m), 7.29-7.36 (2H,m), 7.41-7.46 (1H, m).

Example 350

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.63(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.6 Hz), 4.78-4.87 (1H, m), 5.10(1H, s), 5.67 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.65 (1H, d,J=2.1 Hz), 6.96-6.99 (1H, m), 7.08-7.12 (2H, m), 7.17 (1H, d, J=13.5Hz), 7.25-7.32 (1H, m), 7.35-7.37 (1H, m), 7.42-7.47 (1H, m).

Example 351

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.68(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.84 (2H, m), 5.18(1H, s), 5.72 (1H, d, J=13.5 Hz), 5.81 (1H, dd, J=0.9 Hz, 7.5 Hz), 6.56(1H, d, J=7.2 Hz), 6.76-6.83 (1H, m), 6.90 (1H, t, J=9.0 Hz), 7.07-7.11(1H, m), 7.19 (1H, d, J=7.5 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m).

Example 352

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.1 Hz), 3.59(1H, d, J=13.2 Hz), 4.36 (1H, d, J=9.9 Hz), 4.75-4.85 (2H, m), 5.11 (1H,s), 5.70 (1H, d, J=13.2 Hz), 5.84 (1H, d, J=7.8 Hz), 6.48-6.55 (1H, m),6.71 (1H, dd, J=5.4 Hz, 8.4 Hz), 6.80 (1H, dd, J=2.4 Hz, 9.3 Hz), 7.11(1H, d, J=7.8 Hz), 7.18 (1H, dd, J=0.9 Hz), 7.5 Hz), 7.25-7.30 (1H, m),7.32-7.36 (1H, m), 7.39-7.45 (1H, m).

Example 353

¹H-NMR (CDCl₃) δ: 2.92 (0.66H, s), 3.01 (2.34H, s), 3.59 (0.78H, d,J=13.5 Hz), 3.67 (0.22H, d, J=13.8 Hz), 4.18 (0.22H, d, J=13.2 Hz), 4.21(0.78H, d, J=12.9 Hz), 5.03 (1H, J=12.9 Hz), 5.05 (0.22H, s), 5.10(0.78H, s), 5.62 (0.78H, d, J=13.5 Hz), 5.76-5.82 (0.44H, m), 5.87(0.78H, d, J=7.8 Hz), 6.62 (0.78H, brs), 6.68 (0.22H, d, J=8.1 Hz), 6.85(0.22H, d, J=7.8 Hz), 6.98-7.04 (1.56H, m), 7.11-7.39 (3H, m), 7.44-7.49(1H, m).

Example 354

¹H-NMR (CDCl₃) δ: 2.89 (0.48H, s), 3.00 (2.52H, s), 3.64 (0.84H, d,J=13.5 Hz), 3.71 (0.16H, d, J=13.8 Hz), 4.21 (1H, d, J=12.9 Hz), 4.94(0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=12.9 Hz), 5.10 (0.16H, s), 5.19(0.84H, s), 5.65 (0.84H, d, J=7.5 Hz), 5.77-5.85 (1.32H, m), 6.52(0.84H, d, J=7.8 Hz), 6.64 (0.16H, d, J=7.8 Hz), 6.77-6.84 (1H, m),6.89-6.95 (1H, m), 6.99 (1H, d, J=7.8 Hz), 7.07-7.25 (1H, m), 7.29-7.38(2H, m), 7.42-7.47 (1H, m).

Example 355

¹H-NMR (CDCl₃) δ: 2.91 (0.48H, s), 3.00 (2.52H, s), 3.56 (d, J=13.8 Hz),3.62 (0.16H, d, J=13.8 Hz), 4.18 (0.16H, d, J=12.9 Hz), 4.20 (0.84H, d,J=12.9 Hz), 4.96 (0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=13.8 Hz), 5.03(0.16H, s), 5.12 (0.84H, s), 5.64 (0.84H, d, J=13.5 Hz), 5.78-5.87(0.32H, m), 5.89 (0.84H, d, J=7.8 Hz), 6.50-6.56 (0.84H, m), 6.63-6.69(1.16H, m), 6.84 (1H, dd, J=2.4 Hz, 9.3 Hz), 6.94-6.97 (0.16H, m), 7.02(0.84H, d, J=7.5 Hz), 7.13-7.23 (1H, m), 7.33-7.38 (2H, m), 7.42-7.47(1H, m).

Example 356

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=6.9 Hz), 2.24(3H, s), 3.68 (1H, d, J=13.2 Hz), 4.38 (1H, d, J=13.2 Hz), 4.76-4.85(1H, m), 4.80 (1H, d, J=12.6 Hz), 5.14 (1H, s), 5.72 (1H, d, J=12.9 Hz),5.76 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz), 6.72 (1H, t, J=7.5 Hz),6.99 (1H, d, J=6.9 Hz), 7.07 (1H, d, J=7.8 Hz), 7.17-7.27 (2H, m),7.33-7.42 (2H, m).

Example 357

¹H-NMR (CDCl₃) δ: 1.10 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.58(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.87 (1H, m), 4.85(1H, d, J=12.6 Hz), 5.06 (1H, s), 5.65 (1H, d, J=13.2 Hz), 5.79 (1H, d,J=7.5 Hz), 6.54 (1H, s), 6.89 (1H, dd, J=1.5 Hz, 8.4 Hz), 6.95 (1H, d,J=7.8 Hz), 7.14-7.19 (1H, m), 7.22-7.28 (1H, m), 7.33-7.43 (2H, m).

Example 358

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 2.20(3H, s), 2.23 (3H, s), 3.77 (1H, d, J=12.6 Hz), 4.47 (1H, d, J=12.9 Hz),4.78-4.86 (1H, m), 4.88 (1H, 12.9 Hz), 5.49 (1H, d, J=12.9 Hz), 5.83(1H, d, J=11.1 Hz), 5.85 (1H, d, J=9.0 Hz), 6.64 (1H, d, J=7.8 Hz), 6.86(1H, J=7.8 Hz), 7.16-7.40 (5H, m).

Example 359

¹H-NMR (DMSO-d₆) δ: 1.94 (3H, s), 3.07 (1H, m), 3.98-4.12 (4H, m), 4.25(2H, d, J=13.4 Hz), 5.13 (2H, d, J=13.3 Hz), 5.56 (1H, s), 5.66 (1H, d,J=13.5 Hz), 5.68 (1H, t, J=7.8 Hz), 6.87-7.51 (8H, m).

Example 360

Compound 325 (46.0 mg, 0.0960 mmol) was dissolved in methanol (0.5 ml)and tetrahydrofuran (0.5 ml), a 2N aqueous sodium hydroxide solution(0.241 ml, 0.482 mmol) was added, and the mixture was stirred for 30minutes. To the reaction solution was added dilute hydrochloric acid tomake the solution acidic, and the mixture was extracted with chloroform.The organic layer was dried with sodium sulfate, and the reactionsolution was concentrated under reduced pressure. To the resultingcompound 360 were added n-hexane-diethyl ether, and the precipitatedresidue was filtered to obtain 33 mg of a white solid.

¹H-NMR (DMSO-d₆) δ: 2.85-2.94 (1H, m), 3.52 (2H, m), 3.89 (1H, d, J=13.4Hz), 3.98 (1H, td, J=9.1, 4.5 Hz), 4.24 (1H, d, J=13.6 Hz), 4.84 (1H,brs), 5.16 (1H, d, J=13.6 Hz), 5.48 (1H, s), 5.65 (2H, m), 6.86-7.55(9H, m).

MS: m/z=436 [M+H]⁺.

Using ester bodies synthesized according to Examples 107, 246 and 285,and according to the method of Example 320, compounds 361 to 382 weresynthesized.

Example 361

¹H-NMR (DMSO-d₆) δ: 2.82 (3H, m), 3.49 (1H, brs), 3.71 (1H, dt, J=16.7,5.0 Hz), 4.03 (1H, t, J=7.8 Hz), 4.08-4.15 (2H, m), 4.79 (1H, brs), 5.01(1H, d, J=13.4 Hz), 5.25 (1H, s), 5.51 (1H, d, J=7.6 Hz), 6.72-7.41 (9H,m).

Example 362

MS: m/z=432 [M+H]⁺.

Example 363

MS: m/z=450 [M+H]⁺.

Example 364

MS: m/z=448 [M+H]⁺.

Example 365

MS: m/z=466 [M+H]⁺.

Example 366

MS: m/z=466 [M+H]⁺.

Example 367

MS: m/z=512 [M+H]⁺.

Example 368

MS: m/z=406 [M+H]⁺.

Example 369

MS: m/z=420 [M+H]⁺.

Example 370

¹H-NMR (CDCl₃) δ: 1.23 (3H, s), 1.24 (3H, s), 2.43 (1H, d, J=13.7 Hz),2.81-2.91 (1H, m), 2.96-3.10 (1H, m), 3.61-3.72 (1H, m), 4.02-4.14 (1H,m), 4.15 (1H, d, J=13.7 Hz), 4.42 (1H, d, J=14.0 Hz), 4.95 (1H, s), 5.15(1H, d, J=13.5 Hz), 5.74 (1H, d, J=7.7 Hz), 6.54-6.61 (2H, m), 6.86-6.94(1H, m), 7.11-7.39 (8H, m).

MS: m/z=446 [M+H]⁺.

Example 371

¹H-NMR (CDCl₃) δ: 1.24 (3H, s), 1.26 (3H, s), 2.52 (1H, d, J=14.0 Hz),3.56 (1H, d, J=13.7 Hz), 4.34 (1H, d, J=13.5 Hz), 4.36 (1H, d, J=13.5Hz), 5.04 (1H, s), 5.23 (1H, d, J=13.7 Hz), 5.63 (1H, d, J=13.5 Hz),5.84 (1H, d, J=7.7 Hz), 6.65 (1H, d, J=7.7 Hz), 6.76-6.84 (1H, m),7.03-7.18 (5H, m), 7.27-7.47 (4H, m).

MS: m/z=464 [M+H]⁺.

Example 372

¹H-NMR (CDCl₃) δ: 1.21-1.68 (10H, m), 2.47 (1H, d, J=13.7 Hz), 3.55 (1H,d, J=13.5 Hz), 4.34 (1H, d, J=13.6 Hz), 4.35 (1H, d, J=13.6 Hz), 5.03(1H, s), 5.25 (1H, d, J=13.5 Hz), 5.63 (1H, d, J=13.5 Hz), 5.79 (1H, d,J=7.7 Hz), 6.64 (1H, d, J=7.4 Hz), 6.76-6.84 (1H, m), 7.03 (1H, d, J=7.7Hz), 7.06-7.10 (2H, m), 7.15 (1H, d, J=7.1 Hz), 7.28-7.37 (2H, m),7.37-7.46 (1H, m).

MS: m/z=504 [M+H]⁺.

Example 373

MS: m/z=450 [M+H]⁺.

Example 374

MS: m/z=492 [M+H]⁺.

Example 375

MS: m/z=445 [M+H]⁺.

Example 376

MS: m/z=512 [M+H]⁺.

Example 377

MS: m/z=492 [M+H]⁺.

Example 378

MS: m/z=478 [M+H]⁺

Example 379

MS: m/z=478 [M+H]⁺

Example 380

MS: m/z=492 [M+H]⁺

Example 381

MS: m/z=492 [M+H]⁺

Example 382

¹H-NMR (DMSO-d₆) δ: 2.76-2.85 (1H, m), 3.58 (2H, m), 3.92 (1H, m), 3.98(1H, d, J=13.5 Hz), 4.18 (1H, d, J=13.6 Hz), 4.80 (1H, brs), 5.10 (1H,t, J=8.8 Hz), 5.50-5.68 (3H, m), 6.87-7.52 (8H, m).

Example 383

First Step

Compound 383A (1.00 g, 4.42 mmol) was dissolved in dichloromethane (50ml), mCPBA (2.67 g, 15.5 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 4 hours. To the reaction solution wasadded an aqueous sodium sulfite solution, and the mixture was extractedwith dichloromethane. The organic layer was washed with an aqueoussodium bicarbonate solution, and dried with sodium sulfate, and thesolvent was distilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.06 g of a white solid 383B.

¹H-NMR (CDCl₃) δ: 4.81 (2H, s), 7.29-8.12 (6H, m).

Second Step

To compound 383B (1.05 g, 4.07 mmol) was added methanol (11 ml), sodiumborohydride (185 mg, 4.88 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 30 minutes. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.01 g of a white solid 383C.

¹H-NMR (CDCl₃) δ: 2.84 (1H, d, J=3.7 Hz), 4.76 (1H, d, J=14.6 Hz), 5.25(1H, d, J=14.6 Hz), 6.23 (1H, d, J=3.7 Hz), 7.28-7.96 (8H, m).

Third Step

According to Example 107, compound 383 was synthesized by the sameprocedure.

MS: m/z=466 [M+H]⁺.

Using intermediates corresponding to 383A to 383C which are commerciallyavailable or known in the references, and according to the method ofExample 383, compounds 384 to 389 were synthesized.

Example 384

¹H-NMR (CDCl₃) δ: 1.12-1.25 (6H, m), 2.87-3.26 (3H, m), 3.42-3.67 (1H,m), 4.00-4.08 (1H, m), 4.28-4.35 (1H, m), 4.56-4.83 (3H, m), 5.10-5.30(1H, m), 5.89-6.11 (1H, m), 6.55-6.63 (0.5H, m), 6.71-6.75 (0.5H, m),6.84-6.94 (1H, m), 7.03-7.47 (4H, m), 8.18-8.20 (0.5H, m), 8.48-8.49(0.5H, m).

Example 385

¹H-NMR (CDCl₃) δ: 0.59 (3H, d, J=6.6 Hz), 1.07-1.14 (4H, m), 1.19-1.28(1H, m), 2.22-2.32 (1H, m), 2.73-3.12 (3H, m), 4.71-4.81 (1H, m), 4.83(1H, d, J=12.9 Hz), 4.96 (1H, d, J=12.9 Hz), 5.88 (1H, d, J=7.5 Hz),5.89 (1H, s), 6.89 (1H, m), 7.00-7.04 (2H, m), 7.08-7.18 (2H, m),7.22-7.27 (1H, m), 7.38 (1H, d, J=7.5 Hz), 7.58-7.61 (1H, m), 7.79 (1H,d, J=7.5 Hz).

Example 386

¹H-NMR (CDCl₃) δ: 0.95 (3H, d, J=6.9 Hz), 1.17 (3H, d, 6.9 Hz), 3.34(2H, d, J=12.3 Hz), 4.39 (1H, d, J=12.9 Hz), 4.56-4.65 (1H, m), 4.85(1H, d, J=12.9 Hz), 4.93 (1H, m), 5.77 (1H, d, J=7.5 Hz), 6.77-6.81 (1H,m), 6.79 (1H, d, J=7.5 Hz), 7.00-7.05 (1H, m), 7.21-7.29 (2H, m),7.32-7.42 (3H, m).

Example 387

¹H-NMR (CDCl₃) δ: 1.06-1.17 (6H, m), 4.02-4.17 (1H, m), 4.61-4.78 (2H,m), 5.16 (1H, d, J=5.1 Hz), 5.72 (1H, t, J=8.1 Hz), 6.54 (0.5H, d, J=7.8Hz), 6.84 (0.5H, d, J=7.8 Hz), 6.91-7.08 (2H, m), 7.16-7.47 (4H, m),7.56-7.59 (1H, m), 8.00 (0.5H, J=6.3 Hz), 8.09-8.12 (0.5H, m), 8.51(0.5H, s), 8.68 (0.5H, s).

Example 388

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=6.9 Hz), 1.25 (3H, d, J=6.9 Hz),2.76-2.91 (2H, m), 3.23-3.31 (1H, m), 4.17-4.33 (2H, m), 4, 54-4.84 (2H,m), 5.18 (1H, s), 5.87 (1H, d, J=7.8 Hz), 6.70 (1H, d, J=5.1 Hz), 6.86(1H, d, J=7.8 Hz), 7.04 (1H, d, J=5.1 Hz), 7.19-7.25 (2H, m), 7.32-7.38(2H, m).

Example 389

¹H-NMR (DMSO-d₆) δ: 1.04-1.20 (6H, m), 2.83-3.02 (1H, m), 3.46-3.57 (1H,m), 3.75-3.85 (1H, m), 4.13-4.26 (1H, m), 4.32-4.50 (1H, m), 4.56-4.62(1H, m), 4.89 (1H, d, J=13.2 Hz), 5.36 (1H, s), 5.44-5.50 (1H, m), 6.73(1H, d, J=7.8 Hz), 6.86 (1H, t, J=7.5 Hz), 6.95-6.98 (1H, m), 7.09-6.54(5H, m).

Example 390

First Step.

Compound 390A (14.8 g, 115 mmol) was added to methanol (200 ml), sodiummethoxide (28% methanol solution, 22.2 g, 115 mmol) was added at roomtemperature, and the mixture was stirred for 1 hour. The solvent wasdistilled off under reduced pressure to obtain 17.3 g of a white solid.To 5.61 g of it was added phthalide (5.00 g, 37.3 mmol), and the mixturewas stirred at 200° C. for 1 hour. The reaction solution was poured intowater, the mixture was made acidic with hydrochloric acid, and thegenerated white precipitate was filtered. This was dissolved inchloroform, the solution was dried with sodium sulfate, and the solventwas distilled off. To the resulting compound were addedn-hexane-chloroform-diisopropyl ether, and the precipitated residue wasfiltered to obtain 2.44 g of a pale brown solid 390B.

¹H-NMR (CDCl₃) δ: 5.61 (2H, s), 6.92 (1H, td, J=7.6, 1.4 Hz), 7.01 (1H,dd, J=8.3, 1.3 Hz), 7.21 (1H, ddd, J=8.7, 7.0, 1.2 Hz), 7.32-7.54 (2H,m), 7.66 (1H, td, J=7.6, 1.4 Hz), 7.92-7.99 (1H, m), 8.17 (1H, dd,J=7.9, 1.3 Hz).

Second Step

Compound 390B (2.44 g, 9.29 mmol) was dissolved in dichloromethane (30ml), trifluoroacetic acid anhydride (1.44 ml, 10.2 mmol) and borontrifluoride etherate (0.235 ml, 1.86 mmol) were added, and the mixturewas stirred at room temperature for 3 hours. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was washed with 1N hydrochloric acid and an aqueoussaturated sodium chloride solution, and the solvent was distilled off.The resulting crude product was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (4:1, v/v) toobtain 1.76 g of a pale yellow solid 390C.

¹H-NMR (CDCl₃) δ: 5.36 (2H, s), 7.11 (1H, t, J=8.0 Hz), 7.43-7.66 (4H,m), 7.93 (1H, d, J=6.5 Hz), 8.19 (1H, dd, J=8.1, 1.8 Hz).

Third Step

To compound 390C (1.76 g, 7.19 mmol) was added methanol (20 ml), sodiumborohydride (327 mg, 8.63 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 30 minutes. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.44 g of a white solid 390D.

¹H-NMR (CDCl₃) δ: 2.75 (1H, d, J=5.0 Hz), 5.18 (1H, d, J=13.6 Hz), 5.69(1H, d, J=5.0 Hz), 5.89 (1H, d, J=13.6 Hz), 6.93 (1H, t, J=7.9 Hz),7.19-7.43 (6H, m).

Fourth Step

Compound 390 was synthesized by the same procedure as that of Example107.

MS: m/z=452 [M+H]⁺.

Using amines which are commercially available or known in the referencesand intermediates corresponding to 390A to 390D which are commerciallyavailable or known in the references, and according to the method ofExample 390, compounds 391 to 412 were synthesized.

Example 391

MS: m/z=418 [M+H]⁺.

Example 392

MS: m/z=416 [M+H]⁺.

Example 393

MS: m/z=458 [M+H]⁺.

Example 394

MS: m/z=434 [M+H]⁺.

Example 395

MS: m/z=390 [M+H]⁺.

Example 396

MS: m/z=468 [M+H]⁺

Example 397

MS: m/z=452 [M+H]⁺

Example 398

¹H-NMR (CDCl₃) δ: 1.12-1.32 (6H, m), 4.25 (0.52H, d, J=12.9 Hz), 4.41(0.48H, d, J=13.2 Hz), 4.58-4.79 (2H, m), 4.92-5.03 (2H, m), 5.73(0.48H, d, J=7.8 Hz), 5.89 (0.52H, d, J=7.8 Hz), 6.12 (0.48H, d, J=12Hz), 6.46-6.58 (1.52H, m), 6.74-6.78 (1H, m), 6.98 (1H, t, J=7.5 Hz),7.10-7.14 (1H, m), 7.20-7.50 (4H, m).

Example 399

¹H-NMR (CDCl₃) δ: 1.12-1.31 (6H, m), 4.25 (0.75H, d, J=12.9 Hz), 4.43(0.25H, d, J=12.9 Hz), 4.53-4.60 (0.50H, m), 4.67-4.78 (1.5H, m),4.90-5.05 (2H, m), 5.70 (0.25H, d, J=7.8 Hz, 5.86 (0.75H, d, J=7.5 Hz),6.18 (0.25H, d, J=13.5 Hz), 6.36-6.42 (0.75H, m), 6.49-6.56 (2H, m),6.69-6.80 (1H, m), 6.94 (1H, d, J=7.8 Hz), 7.10-7.19 (0.25H, m),7.21-7.50 (3.75H, m).

Example 400

MS: m/z=452 [M+H]⁺

Example 401

MS: m/z=452 [M+H]⁺

Example 402

MS: m/z=470 [M+H]⁺

Example 403

MS: m/z=436 [M+H]⁺

Example 404

MS: m/z=452 [M+H]⁺

Example 405

MS: m/z=452 [M+H]⁺

Example 406

MS: m/z=490 [M+H]⁺

Example 407

MS: m/z=436 [M+H]⁺

Example 408

MS: m/z=452 [M+H]⁺

Example 409

MS: m/z=452 [M+H]⁺

Example 410

MS: m/z=490 [M+H]⁺

Example 411

MS: m/z=506 [M+H]⁺

Example 412

¹H-NMR (CDCl₃) δ: 1.13-1.31 (12H, m), 3.28-3.37 (0.50H, m), 3.44-3.53(0.50H, m), 4.29-4.36 (1H, m), 4.65-4.76 (2H, m), 4.98-5.05 (2H, m),6.37 (0.5H, d, J=12.9 Hz), 6.45 (0.5H, d, J=7.5 Hz), 6.67 (0.5H, t,J=7.8 Hz), 6.81 (0.5H, 7.8 Hz), 6.98-7.08 (2H, m), 7.14 (0.5Hm d, J=7.8Hz), 7.22-7.45 (2.5H, m).

Example 413, Example 414

First Step

Compound 413A (200 mg, 0.544 mmol) obtained by the same procedure asthat of Example 95, and 6,11-dihydrodibenzo[b,e]thiepin-11-ol (124 mg0.554 mmol) were dissolved in acetic acid (8 ml), and concentratedsulfuric acid (2 ml) was added dropwise under water-cooling. After themixture was stirred at room temperature for 30 minutes, water was added,and the mixture was extracted with ethyl acetate. The organic layer wasdried with sodium sulfate, and the solvent was distilled off underreduced pressure to obtain a crude product of 413B.

Second Step

Compound 413B obtained in the first step was dissolved indichloromethane (2 ml), acetic acid anhydride (0.154 ml, 1.63 mmol),triethylamine (0.226 ml, 1.63 mmol) and 4-(dimethylamino)pyridine (cat.)were added, and the mixture was stirred at room temperature for 30minutes. The solvent was distilled off, the resulting crude product waspurified by silica gel column chromatography, and eluted withchloroform-methanol (97:3, v/v), and diastereomers were resolved. Theywere dissolved in methanol (1 ml) and tetrahydrofuran (1 ml),respectively, a 2N aqueous sodium hydroxide solution (0.198 ml, 0.397mmol) was added, and the mixture was stirred at room temperature for 30minutes. The reaction solution was poured into water, and the mixturewas made acidic with hydrochloric acid, and extracted with ethylacetate. The organic layer was dried with sodium sulfate, and thesolvent was distilled off under reduced pressure. To the resultingcompound were added ethyl acetate-diethyl ether, and thefractionation-precipitated residue was filtered to obtain compound 413(22 mg) and compound 414 (20 mg), respectively.

Example 413

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, d, J=7.4 Hz), 3.92 (1H, d, J=13.6 Hz),4.45 (1H, d, J=13.4 Hz), 5.12 (1H, d, J=12.8 Hz), 5.60 (4H, m),6.87-7.60 (9H, m).

MS: m/z=488 [M+H]⁺

Example 414

MS: m/z=488 [M+H]⁺

According to Example 413, compounds 414 to 475 were synthesized usingthe same procedure.

Example 415

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz),4.41 (1H, d, J=13.3 Hz), 5.07 (1H, d, J=13.0 Hz), 5.42-5.52 (1H, m),5.62 (3H, m), 6.82-7.56 (9H, m).

MS: m/z=488 [M+H]⁺

Example 416

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz),4.44 (1H, d, J=12.7 Hz), 5.15 (1H, d, J=12.5 Hz), 5.16 (1H, m), 5.29(1H, s), 5.57 (1H, d, J=13.4 Hz), 5.64 (1H, d, J=7.8 Hz), 6.81-7.45 (9H,m).

MS: m/z=488 [M+H]⁺

Example 417

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.2 Hz), 4.32 (1H, d, J=13.9 Hz), 4.49(1H, d, J=13.1 Hz), 4.90 (1H, d, J=13.3 Hz), 5.15 (1H, s), 5.47-5.65(2H, m), 5.83 (1H, d, J=8.1 Hz), 6.69 (1H, d, J=6.5 Hz), 6.80-6.87 (1H,m), 7.07-7.24 (5H, m), 7.54 (1H, d, J=7.9 Hz).

MS: m/z=522 [M+H]⁺.

Example 418

¹H-NMR (CDCl₃) δ: 1.48 (3H, d, J=7.1 Hz), 3.63 (1H, d, J=13.2 Hz), 4.49(1H, d, J=12.6 Hz), 5.03 (1H, s), 5.28-5.45 (2H, m), 5.53 (1H, d, J=13.5Hz), 5.73 (1H, d, J=7.7 Hz), 6.50 (1H, dd, J=8.7, 2.6 Hz), 6.79-6.86(1H, m), 6.90 (1H, d, J=9.1 Hz), 7.02 (1H, dd, J=8.8, 5.2 Hz), 7.10 (1H,ddd, J=8.1, 2.5, 1.2 Hz), 7.25 (1H, d, J=7.7 Hz), 7.30 (1H, dd, J=8.5,5.5 Hz).

MS: m/z=524 [M+H]⁺.

Example 419

¹H-NMR (CDCl₃) δ: 1.50 (3H, d, J=7.1 Hz), 4.28 (1H, d, J=13.7 Hz), 4.50(1H, d, J=12.4 Hz), 5.17 (1H, s), 5.26-5.44 (2H, m), 5.60-5.69 (2H, m),6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.01-7.21 (5H, m), 7.48 (1H,d, J=8.0 Hz).

MS: m/z=522 [M+H]⁺.

Example 420

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=7.4 Hz), 3.51 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.6 Hz), 5.12 (1H, s), 5.28-5.44 (2H, m), 5.60-5.70 (2H, m),6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.00-7.06 (2H, m), 7.10 (1H,d, J=8.5 Hz), 7.14 (1H, d, J=8.0 Hz), 7.23 (1H, dd, J=8.2, 2.2 Hz), 7.31(1H, d, J=1.9 Hz).

MS: m/z=522 [M+H]⁺.

Example 421

¹H-NMR (CDCl₃) δ: 1.53 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.4 Hz), 4.51(1H, d, J=12.6 Hz), 5.12 (1H, s), 5.30-5.48 (2H, m), 5.62-5.70 (2H, m),6.71 (1H, d, J=7.7 Hz), 6.80-6.83 (1H, m), 7.07-7.11 (2H, m), 7.18 (1H,d, J=7.7 Hz), 7.22 (1H, s), 7.28 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.1Hz).

MS: m/z=522 [M+H]⁺.

Example 422

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.4 Hz), 5.12 (1H, s), 5.29-5.39 (2H, m), 5.66 (1H, d, J=13.5Hz), 5.73 (1H, d, J=7.7 Hz), 6.61 (1H, d, J=8.2 Hz), 6.73 (1H, dd,J=8.2, 2.2 Hz), 7.04 (1H, d, J=2.2 Hz), 7.12-7.20 (2H, m), 7.23-7.27(1H, m), 7.31 (1H, d, J=6.3 Hz), 7.36-7.44 (1H, m).

MS: m/z=522 [M+H]⁺.

Example 423

¹H-NMR (CDCl₃) δ: 1.47 (3H, d, J=7.1 Hz), 3.69 (1H, d, J=13.5 Hz), 4.49(1H, d, J=12.6 Hz), 5.21 (1H, s), 5.27 (1H, d, J=12.6 Hz), 5.30-5.40(1H, m), 5.70 (1H, d, J=7.7 Hz), 5.75 (1H, d, J=13.5 Hz), 6.65 (1H, dd,J=7.8, 1.5 Hz), 6.73 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=7.7 Hz),7.15-7.22 (2H, m), 7.25-7.29 (1H, m), 7.32 (1H, d, J=8.0 Hz), 7.37-7.45(1H, m).

MS: m/z=522 [M+H]⁺.

Example 424

MS: m/z=490 [M+H]⁺.

Example 425

MS: m/z=490 [M+H]⁺.

Example 426

MS: m/z=490 [M+H]⁺.

Example 427

¹HNMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 3.64 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.8 Hz), 4.88 (1H, d, J=12.8 Hz), 5.08 (1H, s), 5.51 (1H, m),5.60 (1H, d, J=13.5 Hz), 5.93 (1H, d, J=8.1 Hz), 6.58 (1H, d, J=8.1 Hz),6.95 (1H, dd, J=2.0, 8.1 Hz), 7.18 (2H, m), 7.29 (1H, m), 7.37-7.45 (2H,m).

Example 428

¹HNMR (CDCl₃) δ: 1.41 (3H, d, J=7.5 Hz), 3.61 (1H, d, J=13.4 Hz), 4.55(1H, d, J=12.5 Hz), 5.06 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.34 (1H, m),5.63 (1H, d, J=13.4 Hz), 5.87 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz),6.93 (1H, dd, J=1.8, 8.1 Hz), 7.16-7.41 (5H, m).

Example 429

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.4 Hz), 3.64 (1H, d, J=13.5 Hz), 4.44(1H, d, J=13.2 Hz), 4.87 (1H, d, J=13.2 Hz), 5.44-5.57 (1H, m), 5.68(1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 5.94 (1H, s), 6.78-6.91 (2H,m), 7.08-7.18 (3H, m), 7.28-7.38 (3H, m).

MS: m/z=522 [M+H]⁺.

Example 430

MS: m/z=522 [M+H]⁺.

Example 431

MS: m/z=522 [M+H]⁺.

Example 432

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.4 Hz), 3.70 (1H, d, J=13.5 Hz), 4.43(1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.21 (1H, s), 5.46-5.60(1H, m), 5.70 (1H, d, J=13.5 Hz), 5.84 (1H, d, J=7.7 Hz), 6.73 (1H, d,J=7.1 Hz), 6.82-6.89 (1H, m), 7.08-7.17 (2H, m), 7.22 (1H, d, J=7.7 Hz),7.35 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.67 (1H, s).

MS: m/z=071 [M+H]⁺.

Example 433

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.1 Hz), 3.56 (1H, d, J=13.5 Hz), 4.48(1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.2 Hz), 5.09 (1H, s), 5.46-5.60(1H, m), 5.62 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d,J=7.4 Hz), 6.84 (1H, dt, J=10.0, 3.5 Hz), 7.04-7.14 (3H, m), 7.17 (1H,d, J=7.7 Hz), 7.42 (1H, dd, J=8.0, 1.6 Hz), 7.55 (1H, d, J=1.9 Hz).

MS: m/z=433 [M+H]⁺.

Example 434

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=7.3 Hz), 3.54 (1H, d, J=13.4 Hz), 4.54(1H, d, J=12.5 Hz), 5.10 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.31-5.45(1H, m), 5.65 (1H, d, J=13.3 Hz), 5.73 (1H, d, J=7.8 Hz), 6.71 (1H, d,J=7.8 Hz), 6.77-6.84 (1H, m), 7.03-7.11 (3H, m), 7.22 (1H, d, J=7.6 Hz),7.40 (1H, dd, J=8.2, 2.0 Hz), 7.48 (1H, d, J=2.0 Hz).

MS: m/z=433 [M+H]⁺.

Example 435

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=7.3 Hz), 3.70 (1H, d, J=13.4 Hz), 4.51(1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.19 (1H, s), 5.44-5.58(1H, m), 5.62 (1H, d, J=13.3 Hz), 5.87 (1H, d, J=7.6 Hz), 6.86 (1H, d,J=7.9 Hz), 7.07 (1H, dd, J=8.2, 1.4 Hz), 7.15-7.22 (2H, m), 7.27-7.51(4H, m).

MS: m/z=433 [M+H]⁺.

Example 436

¹H-NMR (CDCl₃) δ: 1.48 (3H, d, J=7.4 Hz), 3.71 (1H, d, J=13.3 Hz), 4.60(1H, d, J=12.6 Hz), 5.21 (1H, d, J=12.6 Hz), 5.29 (1H, s), 5.32-5.46(1H, m), 5.70 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz), 6.91 (1H, d,J=7.9 Hz), 7.08 (1H, d, J=7.4 Hz), 7.20-7.29 (2H, m), 7.33-7.51 (4H, m).

MS: m/z=433 [M+H]⁺.

Example 437

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.3 Hz), 3.60 (1H, d, J=13.6 Hz), 4.46(1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.15 (1H, s), 5.47-5.59(1H, m), 5.68 (1H, d, J=13.4 Hz), 5.83 (1H, d, J=7.6 Hz), 6.70 (1H, d,J=7.3 Hz), 6.80-6.88 (1H, m), 7.07-7.26 (6H, m).

MS: m/z=433 [M+H]⁺.

Example 438

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=7.3 Hz), 3.57 (1H, d, J=13.3 Hz), 4.55(1H, d, J=12.5 Hz), 5.05 (1H, d, J=12.5 Hz), 5.23 (1H, s), 5.32-5.47(1H, m), 5.70 (1H, d, J=13.4 Hz), 5.77 (1H, d, J=7.6 Hz), 6.74 (1H, d,J=7.8 Hz), 6.79-6.87 (1H, m), 7.04-7.26 (6H, m).

MS: m/z=433 [M+H]⁺.

Example 439

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.2 Hz), 2.29 (3H, s), 3.76 (1H, d,J=13.3 Hz), 4.54 (1H, d, J=13.1 Hz), 4.92 (1H, d, J=13.1 Hz), 5.18 (1H,s), 5.50-5.62 (1H, m), 5.71 (1H, d, J=13.4 Hz), 5.84 (1H, d, J=7.7 Hz),6.63 (1H, d, J=7.4 Hz), 6.78 (1H, t, J=7.6 Hz), 7.06 (1H, d, J=7.6 Hz),7.17 (1H, d, J=7.7 Hz), 7.23 (1H, d, J=7.6 Hz), 7.28-7.34 (1H, m),7.39-7.51 (2H, m).

MS: m/z=433 [M+H]⁺.

Example 440

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.2 Hz), 2.27 (3H, s), 3.74 (1H, d,J=13.3 Hz), 4.61 (1H, d, J=12.4 Hz), 5.07 (1H, d, J=12.4 Hz), 5.27 (1H,s), 5.31-5.44 (1H, m), 5.75 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz),6.67 (1H, d, J=7.1 Hz), 6.77 (1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.1 Hz),7.21-7.47 (5H, m).

MS: m/z=433 [M+H]⁺.

Example 441

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.45 (1H, d, J=13.4 Hz), 5.08 (1H, d, J=12.8 Hz), 5.56 (4H, dm),6.84-7.54 (8H, m).

Example 442

¹H-NMR (DMSO-d₆) δ: 1.37 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.4 Hz),4.48 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=12.9 Hz), 5.22 (1H, m), 5.38(1H, s), 5.52 (1H, d, J=13.4 Hz), 5.67 (1H, d, J=7.6 Hz), 6.87-7.57 (8H,m).

Example 443

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=7.2 Hz), 3.92 (1H, d, J=13.4 Hz),4.43 (1H, d, J=13.1 Hz), 5.05 (1H, d, J=13.0 Hz), 5.54 (4H, m), 7.29(8H, m).

MS: m/z=522 [M+H]⁺

Example 444

¹H-NMR (DMSO-d₆) δ: 1.13 (3H, d, J=7.0 Hz), 4.00 (1H, d, J=14.2 Hz),4.40 (1H, d, J=13.3 Hz), 5.05 (1H, d, J=13.3 Hz), 5.44 (1H, m),5.62-5.71 (3H, m), 6.82-7.56 (8H, m).

MS: m/z=506 [M+H]⁺

Example 445

¹H-NMR (DMSO-d₆) δ: 1.23 (3H, d, J=7.2 Hz), 4.14 (1H, d, J=13.8 Hz),4.60 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.3 Hz), 5.48 (1H, d, J=15.6Hz) 5.49 (1H, m), 5.69 (1H, d, J=7.9 Hz), 5.70 (1H, s), 6.89-7.47 (8H,m).

MS: m/z=506 [M+H]⁺

Example 446

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.9 Hz), 3.93 (1H, d, J=13.1 Hz),4.49 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.7 Hz), 5.57 (4H, m),6.87-7.61 (8H, m).

MS: m/z=522 [M+H]⁺

Example 447

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.3 Hz),4.48 (1H, d, J=12.9 Hz), 5.21 (1H, d, J=14.4 Hz), 5.22 (1H, m), 5.39(1H, s), 5.52 (1H, d, J=13.6 Hz), 5.67 (1H, d, J=7.6 Hz), 6.88-7.57 (8H,m).

MS: m/z=506 [M+H]⁺

Example 448

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.44 (1H, d, J=13.3 Hz), 5.12 (1H, d, J=13.1 Hz), 5.46-5.68 (3H, m),5.76 (1H, d, J=7.6 Hz), 7.27 (8H, m).

MS: m/z=506 [M+H]⁺

Example 449

¹H-NMR (DMSO-d₆) δ: 1.14 (3H, d, J=7.2 Hz), 3.93 (1H, d, J=13.3 Hz),4.40 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.62(1H, d, J=15.6 Hz), 5.64 (1H, s), 5.75 (1H, d, J=7.6 Hz), 6.94-7.55 (8H,m).

MS: m/z=522 [M+H]⁺

Example 450

¹H-NMR (DMSO-d₆) δ: 1.14 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz),4.41 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.69(3H, m), 6.88-7.57 (8H, m).

MS: m/z=522 [M+H]⁺

Example 451

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz),4.43 (1H, d, J=13.0 Hz), 5.14 (1H, t, J=12.6 Hz), 5.15 (1H, m), 5.42(1H, s), 5.63 (1H, d, J=13.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.88-7.44 (8H,m).

MS: m/z=522 [M+H]⁺

Example 452

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, d, J=7.2 Hz), 4.14 (1H, d, J=13.9 Hz),4.57 (1H, d, J=13.1 Hz), 5.14 (1H, d, J=13.0 Hz), 5.15 (1H, m), 5.30(1H, d, J=13.0 Hz), 5.40 (1H, s), 5.68 (1H, d, J=7.7 Hz), 6.89-7.38 (8H,m).

MS: m/z=506 [M+H]⁺

Example 453

¹H-NMR (DMSO-d₆) δ: 1.40 (3H, d, J=7.4 Hz), 4.05 (1H, d, J=13.4 Hz),4.47 (1H, d, J=13.1 Hz), 5.18 (1H, m), 5.19 (1H, d, J=13.2 Hz), 5.46(1H, s), 5.65 (1H, d, J=13.4 Hz), 5.74 (1H, d, J=7.6 Hz), 6.89-7.52 (8H,m).

MS: m/z=506 [M+H]⁺

Example 454

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, d, J=7.2 Hz), 3.89 (1H, d, J=13.4 Hz),4.46 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.4 Hz), 5.44-5.66 (4H, m),6.83-7.63 (8H, m).

MS: m/z=506 [M+H]⁺

Example 455

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.5 Hz), 3.92 (1H, d, J=13.3 Hz),4.39 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.3 Hz), 5.47 (1H, m), 5.60(1H, d, J=13.3 Hz), 5.68 (1H, s), 5.72 (1H, d, J=7.6 Hz), 7.07-7.54 (8H,m).

MS: m/z=522 [M+H]⁺

Example 456

¹H-NMR (DMSO-d₆) δ: 1.13 (5H, d, J=6.3 Hz), 4.00 (1H, d, J=13.4 Hz),4.52 (1H, d, J=13.6 Hz), 5.09 (1H, d, J=13.3 Hz), 5.49-5.69 (4H, m),6.84-7.51 (8H, m).

MS: m/z=506 [M+H]⁺

Example 457

¹H-NMR (DMSO-d₆) δ: 1.40 (3H, d, J=7.2 Hz), 4.02 (1H, d, J=13.1 Hz),4.53 (1H, d, J=13.3 Hz), 5.20 (1H, d, J=12.9 Hz), 5.26 (1H, m), 5.67(3H, m), 7.18 (8H, m).

MS: m/z=506 [M+H]⁺

Example 458

¹H-NMR (DMSO-d₆) δ: 1.15 (3H, d, J=7.3 Hz), 3.91 (1H, d, J=13.4 Hz),4.39 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.3 Hz), 5.45 (1H, m), 5.62(1H, s), 5.63 (1H, t, J=13.5 Hz), 5.74 (1H, d, J=7.6 Hz), 6.71-7.55 (8H,m).

MS: m/z=506 [M+H]⁺

Example 459

¹H-NMR (DMSO-d₆) δ: 1.39 (3H, d, J=7.4 Hz), 3.95 (1H, d, J=13.4 Hz),4.46 (1H, d, J=12.9 Hz), 5.19 (1H, d, J=13.1 Hz), 5.20 (1H, m), 5.41(1H, s), 5.62 (1H, d, J=13.4 Hz), 5.76 (1H, d, J=7.7 Hz), 6.72-7.50 (8H,m).

MS: m/z=506 [M+H]⁺

Example 460

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.50 (1H, d, J=13.1 Hz), 5.17 (1H, d, J=12.4 Hz), 5.18 (1H, m), 5.39(1H, s), 5.60-5.69 (2H, m), 6.87-7.42 (8H, m).

MS: m/z=506 [M+H]⁺

Example 461

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 3.91 (1H, d, J=13.0 Hz),4.43 (1H, d, J=13.1 Hz), 5.15 (1H, d, J=12.8 Hz), 5.16 (1H, m), 5.41(1H, s), 5.47 (1H, d, J=13.0 Hz), 5.69 (1H, d, J=7.6 Hz), 7.00-7.45 (8H,m).

MS: m/z=506 [M+H]⁺.

Example 462

¹H-NMR (DMSO-d₆) δ: 1.21 (3H, d, J=7.3 Hz), 3.97 (1H, d, J=13.3 Hz),4.46 (1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.6 Hz), 5.50 (1H, m), 5.51(1H, d, J=12.8 Hz), 5.65 (1H, s), 5.72 (1H, d, J=7.6 Hz), 6.85-7.55 (7H,m).

MS: m/z=524 [M+H]⁺

Example 463

MS: m/z=568 [M+H]⁺

Example 464

MS: m/z=502 [M+H]⁺.

Example 465

MS: m/z=502 [M+H]⁺

Example 466

MS: m/z=540 [M+H]⁺

Example 467

MS: m/z=540 [M+H]⁺

Example 468

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=5.8 Hz), 4.20 (1H, d, J=13.6 Hz), 4.58(1H, d, J=12.7 Hz), 4.99 (1H, d, J=12.7 Hz), 5.29-5.42 (3H, m), 5.84(1H, d, J=7.8 Hz), 6.60 (1H, m), 6.79-7.01 (3H, m), 7.19-7.28 (4H, m).

MS: m/z=524 [M+H]⁺.

Example 469

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.6 Hz), 4.21 (1H, d, J=13.9 Hz), 4.48(1H, d, J=13.3 Hz), 4.89 (1H, d, J=13.3 Hz), 5.22 (1H, s), 5.37 (1H, dd,J=2.1, 13.9 Hz), 5.52 (1H, m), 5.86 (1H, d, J=7.6), 6.55 (1H, m), 6.83(1H, m), 6.96 (1H, m), 7.14 (1H, d, J=7.6 Hz), 7.19-7.30 (4H, m).

MS: m/z=524 [M+H]⁺.

Example 470

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 3.65 (1H, d, J=13.5 Hz), 4.47(1H, d, J=13.0 Hz), 4.87 (1H, d, J=13.0 Hz), 5.18 (1H, s), 5.50 (1H, m),5.69 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.8 Hz), 6.53 (1H, m), 6.83 (1H,m), 6.91-7.01 (2H, m), 7.11 (1H, d, J=7.6 Hz), 7.10-7.20 (3H, m).

MS: m/z=524 [M+H]⁺.

Example 471

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=6.1 Hz), 3.63 (1H, d, J=13.5 Hz), 4.56(1H, d, J=12.5 Hz), 5.02 (1H, d, J=12.5 Hz), 5.26 (1H, s), 5.38 (1H, m),5.71 (1H, d, J=13.5 Hz), 5.81 (1H, d, J=7.8 Hz), 6.57 (1H, m), 6.81 (1H,m), 6.91 (1H, m), 6.99 (1H, dd, J=2.6, 8.2 Hz), 7.05 (1H, dd, J=2.6, 8.7Hz), 7.17 (2H, m), 7.19 (1H, d, J=7.6 Hz).

MS: m/z=524 [M+H]⁺.

Example 472

¹HNMR (CDCl₃) δ: 1.21 (3H, d, J=7.4 Hz), 3.66 (1H, d, J=13.5 Hz), 4.47(1H, d, J=13.3 Hz), 4.88 (1H, d, J=13.3 Hz), 5.17 (1H, s), 5.52 (1H, m),5.66 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.7 Hz), 6.54 (1H, m), 6.83 (1H,m), 6.95 (1H, m), 7.11-7.14 (2H, m), 7.23-7.29 (2H, m), 7.41 (1H, d,J=2.0 Hz).

MS: m/z=540 [M+H]⁺.

Example 473

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=6.2 Hz), 3.63 (1H, d, J=13.5 Hz), 4.55(1H, d, J=12.6 Hz), 5.04 (1H, d, J=12.6 Hz), 5.25 (1H, s), 5.38 (1H, m),5.69 (1H, d, J=13.5 Hz), 5.80 (1H, d, J=7.7 Hz), 6.58 (1H, m), 6.82 (1H,m), 6.92 (1H, m), 7.13 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.24-7.29 (2H,m), 7.34 (1H, d, J=2.2 Hz).

MS: m/z=540 [M+H]⁺.

Example 474

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 4.40 (1H, d, J=13.9 Hz), 4.59(1H, d, J=13.0 Hz), 5.02 (1H, d, J=13.0 Hz), 5.31 (1H, s), 5.39 (1H, m),5.66 (1H, d, J=13.9 Hz), 5.84 (1H, d, J=7.8 Hz), 6.58 (1H, m), 6.82 (1H,m), 6.92 (1H, m), 7.10 (1H, m), 7.19 (1H, dd, J=3.7, 7.9 Hz), 7.20-7.26(2H, m), 7.51 (1H, m).

MS: m/z=540 [M+H]⁺.

Example 475

MS: m/z=522 [M+H]⁺.

Example 476

First Step

Compound 476A (3.00 g, 9.83 mmol) synthesized by the same procedure asthat of Example was dissolved in dimethylformamide (30 ml), copper (I)cyanide (2.64 g, 29.5 mmol) was added, and the mixture was stirred at150° C. for 7 hours. The reaction solution was cooled to roomtemperature, and filtered with celite. To the filtrate was added water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v). Tothe resulting compound was added n-hexane, and the precipitated residuewas filtered to obtain 1.81 g of a white solid 476B.

¹H-NMR (CDCl₃) δ: 4.29 (2H, s), 7.28-7.48 (4H, m), 7.78 (2H, t, J=7.5Hz), 8.20 (1H, dd, J=8.1, 1.5 Hz).

Second Step

Compound 476 was synthesized by the same procedure as that of Example107.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.0 Hz), 4.01 (1H, d, J=14.0 Hz),4.65 (1H, d, J=13.7 Hz), 5.04 (1H, d, J=13.3 Hz), 5.45 (1H, t, J=8.1Hz), 5.66 (1H, d, J=7.6 Hz), 5.74 (1H, s), 5.84 (1H, d, J=14.0 Hz),6.87-7.93 (7H, m).

MS: m/z=513 [M+H]⁺

Example 477

First Step

To compound 476B (859 mg, 3.42 mmol) was added concentrated sulfuricacid (13 ml), and the mixture was stirred at room temperature for 18hours, and at 60° C. for 2 hours. The reaction solution was added towater, the mixture was extracted with ethyl acetate, and the organiclayer was dried with sodium sulfate. The solvent was concentrated underreduced pressure to obtain 387 mg of a pale yellow solid. To theresulting compound was added methanol (10 ml), a 10N aqueous sodiumhydroxide solution (6 ml) was added, and the mixture was stirred at 90°C. for 5 hours. The reaction solution was cooled to room temperature,water was added, and the mixture was washed with dichloromethane. To theaqueous layer was added dilute hydrochloric acid, the mixture wasextracted with ethyl acetate, and the organic layer was dried withsodium sulfate. The solvent was concentrated under reduced pressure toobtain 296 mg of a yellow solid 477A.

Second Step

Compound 477A (179 mg, 0.662 mmol) obtained in the first step wasdissolved in dichloromethane (4 ml), dimethylamine hydrochloride (108mg, 1.32 mmol), EDCI (190 mg, 0.993 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (89.0 mg, 0.662 mmol) and triethylamine (0.3 ml)were added, and the mixture was stirred at room temperature for 2 hours.To the reaction solution was added water, the mixture was extracted withethyl acetate, and the organic layer was washed with an aqueous sodiumbicarbonate solution, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography, and eluted withn-hexane-ethyl acetate (1:1, v/v), to obtain 170 mg of a colorless gummysubstance 477B.

¹H-NMR (CDCl₃) δ: 2.99 (3H, s), 3.23 (3H, s), 4.08 (2H, s), 7.28-7.44(5H, m), 7.58 (1H, t, J=4.4 Hz), 8.22 (1H, dd, J=8.1, 1.5 Hz).

Third Step

Compound 477 was synthesized by the same procedure as that of Example107.

MS: m/z=559 [M+H]⁺

Example 478

First Step

Compound 277 (971 mg, 2.11 mmol) was dissolved in dimethylformamide (10ml), cesium carbonate (2.75 g, 8.45 mmol) and benzyl bromide (0.753 ml,6.34 mmol) were added, and the mixture was stirred at room temperaturefor 4 hours. The reaction solution was poured into water, then extractedwith ethyl acetate, and the organic layer was washed with water, anddried with sodium sulfate. The solvent was distilled off under reducedpressure, to the resulting compound were added dichloromethane-diethylether, and the precipitated residue was filtered to obtain 740 mg of awhite solid 478A.

Second Step

Compound 478A (740 mg, 1.35 mmol) was dissolved in tetrahydrofuran (7ml) and methanol (7 ml), a 2N aqueous sodium hydroxide solution (3.37ml, 6.73 mmol) was added, and the mixture was stirred at roomtemperature for 30 minutes. To the reaction solution was added dilutehydrochloric acid to make the solution acidic, the mixture was extractedwith chloroform, and the organic layer was dried with sodium sulfate.The solvent was concentrated under reduced pressure to obtain 618 mg ofa white solid 478B.

MS: m/z=508 [M+H]⁺

Third Step

Compound 478B (505 mg, 0.995 mmol) was dissolved in tetrahydrofuran (10ml), triphenylphosphine (391 mg, 1.49 mmol), phthalimide (220 mg, 1.49mmol) and azodicarboxylic acid diisopropyl ester (0.290 ml, 1.49 mmol)were added, and the mixture was stirred at room temperature for 1 hour.The reaction solution was concentrated under reduced pressure, and theresulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v). To theresulting compound were added dichloromethane-diethyl ether, and theprecipitated residue was filtered to obtain 578 mg of a white solid478C.

MS: m/z=637 [M+H]⁺.

Fourth Step

To compound 478C (667 mg, 1.05 mmol) was added ethanol (10 ml),hydrazine hydrate (0.254 ml, 5.24 mmol) was added, and the mixture wasstirred at 90° C. for 2 hours. The reaction solution was cooled to roomtemperature, chloroform was added, insolubles were removed byfiltration, and the filtrate was concentrated under reduced pressure.The resulting crude product was purified by amino column chromatography,and eluted with chloroform-methanol (97:3, v/v). To the resultingcompound were added dichloromethane-diethyl ether, and the precipitatedresidue was filtered to obtain 462 mg of a white soled 478D.

MS: m/z=507 [M+H]⁺

Fifth Step

To compound 478D (100 mg, 0.197 mmol) were added formic acid (1.0 ml)and an aqueous formalin solution (1.0 ml), and the mixture was stirredat 80° C. for 1 hour. To the reaction solution was added a 1N aqueoussodium hydroxide solution, the mixture was extracted withdichloromethane, and the organic layer was dried with sodium sulfate.The resulting crude product was purified by amino column chromatography,and eluted with chloroform-methanol (97:3, v/v), to obtain 56 mg of acolorless oily substance. This compound was dissolved in acetic acid(2.0 ml), concentrated sulfuric acid (0.5 ml) was added dropwise, andthe mixture was stirred at room temperature for 30 minutes. The reactionsolution was poured into an aqueous sodium bicarbonate solution, and wasextracted with chloroform, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, to theresulting crude product were added dichloromethane-ethyl acetate-diethylether, and the precipitated residue was filtered to obtain 12 mg of awhite solid 478.

MS: m/z=445 [M+H]⁺

Example 479

First Step

To a dichloromethane (50 ml) solution of compound 479A (5.25 g, 11.8mmol) synthesized according to Example 95, DIPEA (6.20 mL, 35.5 mmol)and Boc₂O (5.17 g, 23.7 mmol) was added DMAP (434 mg, 3.55 mmol), andthe mixture was stirred at room temperature for 4 hours. After thereaction solution was concentrated under reduced pressure, the residuewas dissolved in ethyl acetate. The solution was sequentially washedwith 0.5N hydrochloric acid and an aqueous saturated sodium chloridesolution, and dried with sodium sulfate. The solvent was distilled off,and the resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with chloroform and, then, withchloroform-methanol (97:3, v/v). Concentration of an objective fractionafforded 5.22 g of compound 479B as an oil.

MS: m/z=544 [M+H]⁺.

Second Step

To a THF (340 mL) solution of compound 479B (29.7 g, 102 mmol) andacetic acid (29.7 g, 102 mmol) was added TBAF (1M THF solution, 23.6 g,310 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 16 hours. To the reaction solution were added ethylacetate and water, and the ethyl acetate layer was separated, washedwith water, and dried with sodium sulfate. The solvent was distilledoff, and the resulting oil was solidified by addingdichloromethane-ether, to obtain 2.76 g of compound 479C.

MS: m/z=430 [M+H]⁺.

Third Step

To an ethyl acetate (20 mL) suspension of compound 479C (500 mg, 1.16mmol) was added IBX (652 mg, 2.33 mmol), and the mixture was heated tostir for 3 hours. After the reaction solution was diluted with ethylacetate, insolubles were filtered, and the resulting filtrate wassequentially washed with a 1N aqueous sodium hydroxide solution andwater, and dried with sodium sulfate. After the solvent was distilledoff, and the resulting oil was dissolved in THF (5 mL), dimethylamine(2M THF solution, 0.873 mL, 1.75 mmol) and NaBH(OAc)₃ (370 mg, 1.75mmol) were added under ice-cooling, and the mixture was stirred at roomtemperature for 1.5 hours. After 2N hydrochloric acid was added to thereaction solution under ice-cooling, the mixture was made basic with anaqueous sodium bicarbonate solution. This was extracted with chloroform,and dried with sodium sulfate. The solvent was distilled off, and theresulting oil was purified by silica gel chromatography. The materialswere eluted first with chloroform and, then, with chloroform-methanol(93:7, v/v). Concentration of an objective fraction afforded 437 mg ofcompound 479D as an amorphous substance.

MS: m/z=457 [M+H]⁺.

Fourth Step

Compound 479D (430 mg, 0.942 mmol) was dissolved in acetic acid (10 mL),and the solution was heated to stir for 1 hour. The solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (95:5, v/v). Concentration of anobjective fraction afforded 330 mg of compound 479E as an oil.

MS: m/z=357 [M+H]⁺.

Fifth Step

To an acetic acid (2 mL) solution of compound 479E (50 mg, 0.140 mmol)and dibenzosuberol (29.5 mg, 0.140 mmol) was added dropwise sulfuricacid (0.5 mL), and the mixture was stirred for 30 minutes. To thereaction solution were added ethyl acetate and water, thereafter, theaqueous layer was separated, and neutralized with an aqueous sodiumbicarbonate solution. Extraction was performed using the ethyl acetatelayer, and the extract was washed with water, and dried with sodiumsulfate. The solvent was distilled off, and the resulting oil wassolidified by adding ether, to obtain 17.0 mg of compound 479.

MS: m/z=354 [M+H]⁺.

According to Example 478 or Example 479, Examples 480 to 490 weresynthesized using the same procedure.

Example 480

MS: m/z=477 [M+H]⁺.

Example 481

MS: m/z=512 [M+H]⁺.

Example 482

MS: m/z=501 [M+H]⁺.

Example 483

MS: m/z=519 [M+H]⁺.

Example 484

MS: m/z=514 [M+H]⁺.

Example 485

MS: m/z=532 [M+H]⁺

Example 486

MS: m/z=499 [M+H]⁺.

Example 487

MS: m/z=517 [M+H]⁺.

Example 488

MS: m/z=517 [M+H]⁺.

Example 489

MS: m/z=535 [M+H]⁺.

Example 490

MS: m/z=473 [M+H]⁺

Example 491

According to Example 65 and Example 107, compound 491 was synthesized bythe same procedure.

¹H-NMR (DMSO-d₆) δ: 1.10 (3H, d, J=4.0 Hz), 1.12 (3H, d, J=4.6 Hz),2.82-3.06 (2H, m), 3.56 (1H, d, J=17.8 Hz), 4.26 (1H, d, J=13.2 Hz),4.31 (1H, m), 4.51-4.60 (1H, m), 4.97 (1H, d, J=13.1 Hz), 5.39 (1H, s),6.74-7.52 (8H, m).

MS: m/z=460 [M+H]⁺

Example 492

According to Example 65 and Example 107, compound 492 was synthesized bythe same procedure.

MS: m/z=478 [M+H]⁺

Example 493

First Step

A dichloromethane (5 mL) solution of compound 493A (258 mg, 1.30 mmol)was cooled to −50° C., and a toluene solution (1M, 1.96 mL) of DIBAL-Hwas added dropwise over 5 minutes while the same temperature wasretained. After the reaction solution was stirred at the stirred at thesame temperature for 1 hour, temperature was raised to room temperature,and the mixture was stirred for 2.5 hours. To the reaction solution wasadded an aqueous saturated ammonium chloride solution, thereafter, themixture was stirred at room temperature for 1 hour, and insolubles wereremoved by filtration. The dichloromethane layer was separated, and theaqueous layer was extracted with dichloromethane once. The combinedextracts were washed with water three times, washed with an aqueoussaturated sodium chloride solution, and dried. The solvent was distilledoff, and the resulting oil was subjected to silica gel columnchromatography, and eluted with n-hexane-ethyl acetate. Concentration ofan objective fraction afforded 148 mg of compound 493B as an oil.

¹HNMR (CDCl₃) δ: 1.03-1.44 (5H, m), 1.63-1.83 (5H, m), 2.05-2.13 (1H,m), 3.25 (1H, dd, J=9.5 Hz, 3.4 Hz), 7.16-7.19 (2H, ms), 7.27-7.38 (3H,m), 9.69 (1H, d, J=3.5 Hz).

Second Step

According to Example 177, compound 493 was synthesized by the sameprocedure.

MS: m/z=410 [M+H]⁺

Using aldehydes which are commercially available or known in thereferences and hydrazines which are commercially available or known inthe references, and according to Example 493, compounds 494 to 505 weresynthesized.

Example 494

MS: m/z=428 [M+H]⁺

Example 495

MS: m/z=420 [M+H]⁺.

Example 496

MS: m/z=376 [M+H]⁺.

Example 497

MS: m/z=500 [M+H]⁺.

Example 498

MS: m/z=404 [M+H]⁺.

Example 499

MS: m/z=382 [M+H]⁺.

Example 500

MS: m/z=382 [M+H]⁺.

Example 501

MS: m/z=368 [M+H]⁺.

Example 502

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=7.3 Hz),2.87-2.94 (2H, m), 3.10-3.22 (1H, m), 3.79-3.89 (1H, m), 3.98 (1H, d,J=16.9 Hz), 4.17 (1H, d, J=16.8 Hz), 4.28 (1H, d, J=9.8 Hz), 6.04 (1H,d, J=7.2 Hz), 6.54 (2H, t, J=8.1 Hz), 6.73 (1H, d, J=9.8 Hz), 6.95-7.33(6H, m), 7.66 (1H, dd, J=5.3, 3.6 Hz).

MS: m/z=448 [M+H]⁺.

Example 503

MS: m/z=374 [M+H]⁺.

Example 504

MS: m/z=374 [M+H]⁺.

Example 505

MS: m/z=342 [M+H]⁺.

Example 506

According to Example 177, using compound 65B, compound 506 wassynthesized by the same procedure.

MS: m/z=470 [M+H]⁺.

Example 507

According to Example 65, using compound 506, compound 507 wassynthesized by the same procedure.

MS: m/z=446 [M+H]⁺.

Example 508

First Step

Compound 508A (261 mg, 0.475 mmol) which is a synthetic intermediate ofExample 491 was dissolved in dimethyformamide (3 ml), triethylamine(0.132 ml, 0.950 mmol) and ethyl chloroformate (0.0910 ml, 0.950 mmol)were added at 0° C., and the mixture was stirred at room temperature for20 minutes. An aqueous solution (0.5 ml) of sodium borohydride (71.9 mg,1.90 mmol) was added at 0° C., and the mixture was stirred for 30minutes. The reaction solution was poured into water, the mixture wasextracted with ethyl acetate, and the organic layer was dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v). Diethylether was added, and the precipitated residue was filtered to obtain 107mg of a white solid 508B.

MS: m/z=536 [M+H]⁺

Second Step

Compound 508B (100 mg, 0.187 mmol) obtained in the first step wasdissolved in dichloromethane (1 ml), DAST (33.1 mg, 0.205 mmol) wasadded at 0° C., and the mixture was stirred for 30 minutes. The reactionsolution was poured into water, the mixture was extracted withchloroform, and the organic layer was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product was purified by silica gel column chromatography, andeluted with chloroform-methanol (97:3, v/v), to obtain 28 mg of a paleyellow gummy substance 508C.

MS: m/z=538 [M+H]⁺

Third Step

To compound 508C obtained in the second step were added acetic acid (2ml) and concentrated sulfuric acid (0.5 ml), and the mixture was stirredat room temperature for 20 minutes. The reaction solution was pouredinto water, the mixture was extracted with ethyl acetate, and theorganic layer was dried with sodium sulfate. Diethyl ether was added,and the precipitated residue was filtered to obtain 4.5 mg of a whitesolid 508.

MS: m/z=448 [M+H]⁺

Example 509

According to Example 508, compound 509 was synthesized by the sameprocedure.

MS: m/z=466 [M+H]⁺

Example 510

First Step

Compound 510A (36.8 g, 259 mmol) was dissolved in dimethylformamide (380ml), potassium carbonate (39.3 g, 285 mmol) and benzyl bromide (30.7 ml,259 mmol) were added, and the mixture was stirred at 80° C. for 8 hours.The reaction was cooled to room temperature, insolubles were removed byfiltration, and the solvent was distilled off under reduced pressure.Water was added, and the precipitated residue was filtered, and driedunder reduced pressure to obtain 46.21 q of a pale brown solid 510B.

Second Step

To compound 510B (4.79 g, 20.6 mmol) obtained in the first step wasadded dichloromethane (70 ml), triethylamine (4.29 ml, 30.9 mmol) andmethanesulfonyl chloride (1.93 ml, 24.8 mmol) were added at 0° C., andthe mixture was stirred for 30 minutes. The reaction solution was pouredinto an aqueous saturated sodium chloride solution, the mixture wasextracted with dichloromethane, the extract was dried with sodiumsulfate, and the solvent was distilled off under reduced pressure. Tothe resulting compound were added n-hexane-dichloromethane, and theprecipitated residue was filtered to obtain 6.56 g of a white solid.This compound was dissolved in acetonitrile (40 ml), tetrabutylammoniumfluoride (75% aqueous solution, 21.6 g, 61.9 mmol) was added, and themixture was stirred at room temperature for 18 hours. The solvent wasdistilled off under reduced pressure, ethyl acetate was added, and themixture was washed with an aqueous sodium bicarbonate solution. Theorganic layer was dried with sodium sulfate, and distilled off underreduced pressure, and the resulting crude product was purified by silicagel column chromatography, and eluted with n-hexane-ethyl acetate (1:1,v/v), to obtain 2.51 g of a white solid 510C.

¹H-NMR (DMSO-d₆) δ: 4.96 (3H, s), 5.30 (3H, d, J=46.4 Hz), 6.56 (1H, d,J=1.8 Hz), 7.39 (5H, m), 8.30 (1H, s).

Third Step

Compound 510C (2.40 g, 10.3 mmol) obtained in the second step wasdissolved in dichloromethane (40 ml), boron tribromide (1Mdichloromethane solution, 10.3 ml, 10.3 mmol) was added dropwise at 0°C., and the mixture was stirred for 30 minutes. Methanol was added, thesolvent was distilled off under reduced pressure, ethyl acetate wasadded, and the mixture was washed with an aqueous saturated sodiumchloride solution. The organic layer was dried with sodium sulfate, thesolvent was distilled off under reduced pressure, and the resultingsolid was washed with diethyl ether to obtain 940 mg of 510D.

¹H-NMR (CDCl₃) δ: 5.20 (2H, d, J=46.3 Hz), 6.40 (1H, s), 6.62 (1H, s),7.91 (1H, s).

Fourth Step

Compound 510D (940 mg, 6.52 mmol) obtained in the third step wasdissolved in methanol (8 ml), a 2N aqueous sodium hydroxide solution(3.26 ml, 6.52 mmol) and a 37% aqueous formaldehyde solution (1.46 ml,19.6 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 20 hours. To the reaction solution was added an aqueoussaturated ammonium chloride solution, and the solvent was distilled offunder reduced pressure. Hydrochloric acid was added, the mixture wasextracted with chloroform, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, to theresulting compound were added n-hexane-dichloromethane-ethyl acetate,and the precipitated residue was filtered to obtain 858 mg of a paleyellow solid 510E.

¹H-NMR (CDCl₃) δ: 4.73 (2H, s), 5.19 (2H, d, J=46.1 Hz), 6.55 (1H, s).

Fifth Step

Compound 510E (855 mg, 4.91 mmol) obtained in the fourth step wasdissolved in dimethylformamide (10 ml), potassium carbonate (746 mg,5.40 mmol) and benzyl bromide (0.583 ml, 4.91 mmol) were added, and themixture was stirred at 80° C. for 5 hours. Insolubles were removed byfiltration, and the filtrate was distilled off under reduced pressure.The resulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v), toobtain 887 mg of a pale orange solid 510F.

¹H-NMR (CDCl₃) δ: 1.39 (1H, t, J=7.1 Hz), 4.31 (2H, d, J=7.2 Hz), 5.12(2H, dd, J=46.3, 0.7 Hz), 5.23 (2H, s), 6.50 (1H, s), 7.33-7.43 (5H, m).

Sixth Step

Compound 510F (887 mg, 3.36 mmol) obtained in the fifth step wasdissolved in chloroform, manganese dioxide (2.00 g, 23.0 mmol) wasadded, and the mixture was stirred at 80° C. for 2 hours. After cooledto room temperature, the mixture was filtered with celite, and thesolvent was distilled off under reduced pressure to obtain 812 mg of awhite solid 510G.

¹H-NMR (CDCl₃) δ: 5.18 (2H, dd, J=45.8, 0.8 Hz), 5.52 (2H, s), 6.60 (1H,d, J=0.8 Hz), 7.32-7.38 (5H, m), 9.86 (1H, s).

Seventh Step

To compound 510G (884 mg, 3.37 mmol) obtained in the sixth step wereadded acetonitrile and water, monosodium dihydrogen phosphate (809 mg,6.74 mmol) and sodium hypochlorite (1.01 g, 11.1 mmol) were added, andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was concentrated, pH was adjusted to 3 with hydrochloric acid,the mixture was extracted with chloroform, and the extract was driedwith sodium sulfate. The solvent was distilled off under reducedpressure to obtain 404 mg of a white solid 510H.

¹H-NMR (DMSO-d₆) δ: 5.17 (2H, s), 5.38 (2H, d, J=46.2 Hz), 6.73 (1H, d,J=1.5 Hz), 7.34-7.51 (5H, m).

Eighth Step

Compound 510H (402 mg, 1.45 mmol) obtained in the seventh step wasdissolved in dimethylformamide,N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (554 mg, 2.89 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol(195 mg, 1.45 mmol) were added, and the mixture was stirred at roomtemperature for 5 minutes. After propan-2-amine (0.149 ml, 1.73 mmol)was added, the mixture was stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, water wasadded, the mixture was extracted with ethyl acetate, and the organiclayer was washed with an aqueous sodium bicarbonate solution, and driedwith sodium sulfate. The reaction solution was distilled off underreduced pressure, to the resulting compound was added n-hexane, and theprecipitated residue was filtered to obtain 3.56 g of a white solid510I.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 4.05 (1H, m), 5.24 (2H, dd,J=45.9, 0.9 Hz), 5.41 (2H, s), 6.59 (1H, q, J=0.9 Hz), 7.40 (5H, m),7.56 (1H, brs).

Ninth Step

Compound 510I (392 mg, 1.23 mmol) obtained in the eighth step wasdissolved in ethanol (6 ml), aqueous ammonia (4 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was concentrated under reduced pressure, and the resultingcrude product was purified by silica gel column chromatography, andeluted with chloroform-methanol (97:3, v/v), to obtain 333 mg of a whitesolid 510J.

MS: m/z=319 [M+H]⁺

Tenth Step

Compound 510 was synthesized by the same procedure as that of Example95.

MS: m/z=422 [M+H]⁺

Example 511

First Step

A dichloromethane (90 mL) solution of compound 511A (200 mg, 0.664 mmol)and 1,1,3-trimethoxypropane (178.2 mg, 1.33 mmol) was cooled to 1 to 3°C., and a boron trifluoride diethyl ether complex (113 mg, 0.797 mmol)was added dropwise while the same temperature was retained. After thereaction solution was stirred at the same temperature for 30 minutes,saturated sodium bicarbonate water was added. The dichloromethane layerwas separated, and the aqueous layer was extracted with dichloromethanethree times. After the combined extracts were dried with sodium sulfate,the solvent was distilled off, and the resulting oil was purified bysilica gel column chromatography. The materials were eluted firstly withethyl acetate and, then, with ethyl acetate-methanol (3:2, v/v).Concentration of an objective fraction afforded 179.2 mg of compound511B as an oil.

¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J=6.3 Hz), 2.71 (2H, dd, J=6.0 Hz), 3.34(3H, s), 3.64 (2H, t, J=6.0 Hz), 4.06-4.17 (1H, m), 5.23 (2H, s), 6.34(1H, brs), 6.37 (1H, d, J=7.8 Hz), 7.26-7.43 (6H, m), 7.90 (1H, t, J=5.4Hz).

Second Step

A dimethylformamide (3 ml) solution of compound 511B (179.2 mg, 0.482mmol) was cooled to 1 to 3° C., cesium carbonate (786 mg, 2.41 mmol) wasadded while the same temperature was retained, and the mixture wasstirred at the same temperature for 15 minutes. The reaction solutionwas diluted with water, and extracted with chloroform three times. Afterthe combined extracts were dried with sodium sulfate, the solvent wasdistilled off to obtain 130 mg of compound 511C as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 1.59(2H, brs), 3.22-3.41 (2H, m), 3.12 (3H, s), 4.57-4.70 (2H, m), 5.19 (1H,d, J=10.5 Hz), 5.38 (1H, brs), 5.54 (1H, d, J=10.5 Hz), 6.34 (1H, d,J=7.8 Hz), 7.26-7.32 (4H, m), 7.49-7.52 (2H, m).

Third Step

To an acetic acid (2 ml) solution of compound 511C (130 mg, 0.350 mmol)and dibenzosuberol (368 mg, 1.75 mmol) was added dropwise sulfuric acid(0.4 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and extracted with ethyl acetate three times. The extract waswashed with water once, and dried with sodium sulfate, thereafter, thesolvent was distilled off, and the resulting solid was washed withdiisopropyl ether to obtain 65 mg of compound 511 as a solid.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz),1.64-1.74 (1H, m), 1.88-1.99 (1H, m), 2.83 (1H, d, J=4.5 Hz, 4.5 Hz, 9.3Hz), 3.06 (1H, ddd, J=5.6 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.30-3.44(1H, m), 3.50-3.57 (1H, m), 3.78-3.92 (1H, m), 4.28 (1H, ddd, J=4.2 Hz,13.5 Hz, 13.5 Hz), 4.53 (1H, dd, J=3.3 Hz, 10.8 Hz), 4.96 (1H, s), 5.73(1H, d, J=7.5 Hz), 6.61 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=7.5 Hz),6.89-6.93 (1H, m), 7.08-7.36 (6H, m).

Using amines which are commercially available or known in the referencesand acetals which are commercially available or known in the references,and according to Example 511, compounds 512 to 515 were synthesized.

Example 512

MS: m/z=528 [M+H]⁺

Example 513

MS: m/z=528 [M+H]⁺

Example 514

¹H-NMR (CDCl₃) δ: 1.27 (1H, 3H, d, J=6.9 Hz), 1.48 (3H, d, J=6.6 Hz),1.95 (3H, s), 2.63-2.68 (2H, m), 2.84 (1H, ddd, J=4.8 Hz, 9.3 Hz, 9.3Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.60 (1H, ddd, J=4.8Hz, 4.8 Hz, 17.4 Hz), 3.87-3.98 (1H, m), 4.42 (1H, dd, J=6.6 Hz, 8.1Hz), 4.59 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.93 (1H, s), 5.77 (1H,d, J=7.8 Hz), 6.64 (1H, d, J=6.9 Hz), 6.69 (1H, d, J=7.8 Hz), 6.91 (1H,t, J=6.0 Hz), 7.09-7.38 (6H, m).

Example 515

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.9 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 9.3 Hz), 3.07 (1H, ddd, J=4.5 Hz, 13.5 Hz,13.5 Hz), 3.25 (3H, s), 3.22-3.43 (2H, m), 3.55 (1H, ddd, J=4.2 Hz, 4.2Hz, 8.7 Hz), 3.85-3.94 (1H, m), 4.36 (1H, dd, J=5.1 Hz, 14.1 Hz),4.42-4.48 (1H, m), 4.92 (1H, s), 5.78 (1H, d, J=7.5 Hz), 6.59 (1H, d,J=7.8 Hz), 6.64 (1H, d, J=7.5 Hz), 6.91 (1H, t, J=6.9 Hz), 7.09-7.36(6H, m).

Example 516

First Step

To a toluene (3 ml) solution of compound 516A (100 mg, 0.332 mmol) and3-(methylthio)propanal (52 mg, 0.498 mmol) was added acetic acid (30 mg,0.500 mmol), and the mixture was refluxed for 30 minutes. After cooledto room temperature, the solvent was distilled off, and the resultingcrude product was dissolved in dimethylformamide (3 ml). The solutionwas cooled to 1 to 3° C., cesium carbonate (541 mg, 1.66 mmol) was addedwhile the same temperature was retained, and the mixture was stirred atthe same temperature for 30 minutes. The reaction solution was dilutedwith water, and extracted with ethyl acetate three times. The combinedextracts were washed with water three times, and dried with sodiumsulfate, and the solvent was distilled off. The resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with ethyl acetate and, then, with ethyl acetate-methanol (7:3,v/v). Concentration of an objective fraction afforded 84.7 mg ofcompound 516B as an oil.

¹H-NMR (CDCl₃) δ: 1.21 (3H, J=6.9 Hz), 1.28 (3H, d, J=6, 9 Hz),1.31-1.56 (2H, m), 2.05 (3H, s), 2.46 (2H, dd, J=5.4 Hz, 7.8 Hz),4.57-4.71 (2H, m), 5.18 (1H, d, J=10.5 Hz), 5.51 (1H, d, J=10.5 Hz),5.66 (1H, brs), 6.33 (1H, d, J=7.8 Hz), 7.19-7.35 (4H, m), 7.46-7.49(2H, m).

Second Step

Compound 516 was synthesized by the same procedure as that of Example511.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz),1.82-1.89 (2H, m), 1.99 (3H, s), 2.41-2.58 (2H, m), 2.86 (1H, ddd, J=4.5Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd, J=4.5 Hz, 4.5Hz, 17.7 Hz), 4.87-3.96 (1H, m), 4.21 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9Hz), 4.53 (1H, dd, J=5.1 Hz, 8.7 Hz), 4.96 (1H, s), 5.74 (1H, d, J=7.5Hz), 6.62 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=9.0 Hz), 6.89-6.94 (1H, m),7.07-7.37 (6H, m).

Using amines which are commercially available or known in the referencesand aldehydes which are commercially available or known in thereferences, and according to Example 516, compounds 517 to 526 weresynthesized.

Example 517

MS: m/z=500 [M+H]⁺

Example 518

¹H-NMR (CDCl₃) δ: 1.78 (3H, t, J=6.9 Hz), 1.19-1.30 (1H, m), 1.29 (3H,d, J=6.9 Hz), 1.43-1.62 (3H, m), 1.50 (3H, d, J=6.9 Hz), 2.84 (1H, ddd,J=4.5 Hz, 4.5 Hz, 14.1 Hz), 3.00-3.11 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9Hz), 3.52 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.4 Hz), 3.79-3.88 (1H, m),4.23-4.35 (2H, m), 4.96 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.61 (1H, d,J=7.5 Hz), 6.65 (1H, dd, J=1.2 Hz, 7.8 Hz), 6.91 (1H, ddd, J=1.5 Hz, 7.5Hz, 7.5 Hz), 7.08-7.37 (6H, m).

Example 519

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=6.9 Hz), 1.54 (3H, d, J=6.6 Hz), 1.88(1H, ddd, J=3.9 Hz, 3.9 Hz, 14.4 Hz), 2.72 (1H, ddd, J=3.6 Hz, 14.1 Hz,14.1 Hz), 3.15 (1H, ddd, J=4.2 Hz, 4.2 Hz, 16.5 Hz), 3.54 (1H, dd, J=3.0Hz, 14.4 Hz), 3.66 (1H, ddd, J=3.9 Hz, 13.8 Hz, 13.8 Hz), 4.03 (1H, dd,J=10.5 Hz, 14.1 Hz), 4.27-4.26 (1H, m), 4.64 (1H, dd, J=2.7 Hz, 10.5Hz), 4.92 (1H, s), 5.80 (1H, d, J=7.8 Hz), 6.62-6.70 (2H, m), 6.69 (1H,d, J=7.8 Hz), 6.89 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.5 Hz), 7.09-7.25(4H, m), 7.77-7.89 (4H, m).

Example 520

¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=6.6 Hz), 1.54 (3H, d, J=6.6 Hz), 2.83(1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.03-3.14 (1H, m), 3.21 (3H, s),3.30 (3H, s), 3.53 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.61-3.70 (1H,m), 4.18 (1H, d, J=5.4 Hz), 4.26 (1H, d, J=5.4 Hz), 4.45 (1H, ddd, J=4.5Hz, 13.8 Hz, 13.8 Hz), 4.92 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.63 (1H,d, J=7.8 Hz), 6.65 (1H, d, J=6.6 Hz), 6.91 (1H, t, J=6.0 Hz), 7.08-7.36(6H, m).

Example 521

¹H-NMR (CDCl₃) δ: 1.30 (2.52H, d, J=6.9 Hz), 1.36 (0.48H, d, J=6.9 Hz),1.42 (0.48H, d, J=6.9 Hz), 1.50 (2.52H, d, J=6.9 Hz), 1.74-1.98 (1H, m),2.00-2.12 (1H, m), 2.16-2.35 (1H, m), 2.89 (1H, ddd, J=5.1 Hz, 5.1 Hz,13.5 Hz), 3.06 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9H), 3.52 (1H, d, J=4.2Hz, 4.2 Hz, 17.4 Hz), 3.86-3.96 (1H, m), 4.15 (1H, ddd, J=3.9 Hz, 13.5Hz, 13.5 Hz), 4.32 (1H, dd, J=3.9 Hz, 10.8 Hz), 4.48-4.64 (1H, m), 4.97(0.84H, s), 5.30 (0.16H, s), 5.73 (0.84H, d, J=7.8 Hz), 6.20 (0.16H, d,J=7.5 Hz), 6.45 (0.16H, brs), 6.61 (1H, d, J=7.5 Hz), 6.64 (0.84H, d,J=8.7 Hz), 6.92 (1H, t, J=6.3 Hz), 7.10 (1H, d, J=7.5 Hz), 7.15-7.39(3H, m).

Example 522

¹H-NMR (CDCl₃) δ: 1.28 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz),1.54-1.79 (4H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.05 (1H,ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.17 (3H, s), 3.17-3.21 (2H, m), 3.52(1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H, m), 4.22-4.32 (2H,m), 4.96 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.65(1H, d, J=8.1 Hz), 6.92 (1H, t, J=7.2 Hz), 7.07-7.37 (6H, m).

Example 523

¹H-NMR (CDCl₃) δ: 1.19-1.28 (1H, m), 1.28 (3H, d, J=6.9 Hz), 1.40-1.82(4H, m), 1.48 (3H, d, J=6.6 Hz), 2.89-3.00 z81H, m), 3.17 (3H, s),3.20-3.27 (2H, m), 3.31-3.40 (1H, m), 3.44-3.53 (1H, m), 3.86-3.98 (2H,m), 4.38 (1H, dd, J=3.6 Hz, 10.5 Hz), 5.05 (1H, s), 5.84 (1H, d, 7.5Hz), 6.48-6.50 (1H, m), 6.66-6.69 (1H, m), 6.89-7.00 (2H, m), 7.05 (1H,d, 7.2 Hz), 7.11-7.24 (2H, m).

Example 524

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.42-1.83 (4H, m), 1.48 (3H,d, J=6.6 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz), 14.4H), 2.94-3.11 (1H,m), 3.18 (3H, s), 3.21-3.26 (2H, m), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz,18.0 Hz), 3.82-3.91 (1H, m), 4.20-4.33 (2H, m), 5.83 (1H, s), 5.84 (1Hmd, J=7.8 Hz), 6.58-6.72 (2H, m), 6.91-6.94 (1H, m), 7.11-7.30 (4H, m).

Example 525

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.10(3H, s), 2.78 (1H, ddd, J=4.2 Hz, 4.2 Hz, 13.8 Hz), 2.97 (3H, s),3.01-3.13 (2H, m), 3.47 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.65 (1H,dd, J=3.3 Hz, 14.1 Hz), 3.99-4.23 (2H, m), 4.70 (1H, dd, J=3.3 Hz, 10.2Hz), 4.95 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.8 Hz), 6.65(1H, d, J=7.5 Hz), 6.93 (1H, t, J=6.6 Hz), 7.09 (1H, d, J=7.5 Hz),7.15-7.27 (4H, m), 7.30-7.37 (1H, m).

Example 526

¹H-NMR (CDCl₃) δ: 1.57-1.34 (1H, m), 1.29 (3H, d, J=6.9 Hz), 1.41-1.52(1H, m), 1.48 (3H, d, J=6.6 Hz), 1.59-1.81 (2H, m), 2.80 (1H, ddd, 4.5Hz, 4.5 Hz, 14.4 Hz), 3.04 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz),3.14-3.26 (2H, m), 3.18 (3H, s), 3.49 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.7Hz), 3.84-3.93 (1H, m), 4.23-4.34 (2H, m), 4.96 (1H, s), 5.81 (1H, d,J=7.5 Hz), 6.60-6.79 (3H, m), 6.81 (1Hm d, J=9.3 Hz), 6.92 (1H, ddd,J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.19-7.24 (1H, m).

Example 527

First Step

A DMF (0.2 mL) solution of compound 527A (36 mg, 0.09 mmol) synthesizedaccording to the method of synthesizing compound 516 was cooled to 1 to3° C., 5-chlorodibenzosuberane (97 mg, 0.43 mmol) and cesium carbonate(138 mg, 0.43 mmol) were added, and the mixture was stirred at roomtemperature overnight. To the reaction solution was added water, and themixture was distributed between ethyl acetate and water. The organiclayer was washed with an aqueous saturated sodium chloride solution, anddried. The solvent was distilled off, and the resulting oil wassubjected to silica gel column chromatography, and eluted withchloroform-methanol. Concentration of an objective fraction afforded 19mg of compound 527B as an oil.

MS: m/z=616 [M+H]⁺.

Second Step

Compound 527B (19 mg, 0.03 mmol) was dissolved in MeOH (0.6 mL), 10%Pd-C (3 mg) was added, and the mixture was subjected to a catalyticreduction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. The resulting oil was subjected todiol silica gel column chromatography, and eluted withchloroform-methanol. Concentration of an objective fraction afforded 7mg of compound 527 as an oil.

MS: m/z=526 [M+H]⁺.

Using halides which are commercially available or known in thereferences and aldehydes which are commercially available or known inthe references, and according to the method of Example 527, compounds528 to 531 were synthesized.

Example 528

MS: m/z=418 [M+H]⁺

Example 529

MS: m/z=432 [M+H]⁺

Example 530

MS: m/z=459 [M+H]⁺

Example 531

MS: m/z=466 [M+H]⁺

Example 532

First Step

To a methanol (5 ml) solution of compound 519 (440 mg, 0.766 mmol) wasadded hydrazine hydrate (383 mg, 7.66 mmol), and the mixture wasrefluxed for 1 hour. After cooled to room temperature, the precipitatedinsolubles were filtered off. After the solvent was distilled off, theresidue was suspended in ethyl acetate, the insolubles were filteredoff, and the solvent was distilled off. The resulting crude product wassuspended in chloroform, and insolubles were filtered off. The solventwas distilled off, and the resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 190 mg of compound 532 as a solid.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, J=6.9H), 1.46 (3H, d, J=6.6 Hz),2.73-2.90 (3H, m), 3.08 (1H, ddd, J=4.2 Hz, 12.9 Hz, 12.9 Hz), 3.54 (1H,ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.85-3.94 (1H, m), 4.19 (1H, dd, J=7.2Hz, 11.1 Hz), 4.35 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.97 (1H, s),5.74 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.2 Hz),6.92 (1H, t, J=6.3 Hz), 7.09-7.45 (6H, m).

Example 533

Compound 533 was synthesized by the same procedure as that of Example532.

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz),1.45-1.58 (1H, m), 1.62-1.75 (1H, m), 2.61-2.69 (1H, m), 2.71-2.84 (1H,m), 2.88-2.95 (1H, m), 3.16-3.34 (1H, m), 3.60-3.64 (1H, m), 3.92-4.00(1H, m), 4.24-4.33 (1H, m), 4.42-4.46 (1H, dd, J=3.3 Hz, 10.8 Hz), 5.10(1H, s), 5.47 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.88 (1H, t,J=7.5 Hz), 7.02 (1H, d, J=10.8 Hz), 7.09-7.16 (2H, m), 7.19-7.25 (1H,m), 7.33 (2H, d, 4.2 Hz), 7.42 (1H, d, J=7.5 Hz).

Example 534

Compound 534 was synthesized by the same procedure as that of Example532.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.6 Hz),1.32-1.58 (2H, m), 1.77-1.79 (2H, m), 2.64-2.73 (1H, m), 2.79-3.00 (2H,m), 3.88-3.97 (2H, m), 4.19-4.28 (2H, m), 5.15 (1H, s), 5.67 (1H, d,J=7.5 Hz), 5.73 (1H, d, J=7.5 Hz), 6.90 (1H, t, J=6.6 Hz), 7.03 (1H, d,J=7.5 Hz), 7.13-7.32 (3H, m), 7.36 (2H, d, J=4.2 Hz), 7.44 (1H, J=7.2Hz), 7.75 (1H, brs).

Example 535

Compound 535 was synthesized by the same procedure as that of Example532.

¹H-NMR (DMSO-d₆) δ: 1.40-1.52 (1H, m), 1.61-1.72 (1H, m), 2.40-2.49 (1H,m), 2.58-2.62 (1H, m), 2.78-2.86 (1H, m), 2.89-2.95 (1H, m), 2.95 (3H,m), 3.66-3.74 (1H, m), 4.01-4.13 (1H, m), 4.28-4.32 (1H, m), 5.14 (1H,m), 5.51 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.5 Hz), 6.91-6.94 (2H, m),7.14-7.40 (6H, m).

Example 536

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and a 38% aqueous formalin solution (53.5 mg, 0.675 mmol) was cooled to1 to 3° C., sodium triacetoxyhydroborate (42.9 mg, 0.293 mmol) andacetic acid (10 mg, 0.166 mmol) were added while the same temperaturewas retained. After the reaction solution was stirred at the sametemperature for 30 minutes, saturated sodium bicarbonate water wasadded, and the mixture was extracted with ethyl acetate three times. Thecombined extracts were washed with water once, and dried with sodiumsulfate, and the solvent was distilled off. The resulting crude productwas washed with ethyl acetate-diisopropyl ether to obtain 20 mg ofcompound 536 as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.9 Hz), 2.06(6H, s), 2.29 (1H, dd, J=4.5 Hz, 13.2 Hz), 4.23 (1H, dd, J=8.4 Hz, 13.2Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz, 3.06 (1H, J=4.2 Hz, 13.5Hz, 13.5 Hz), 3.55 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H,m), 4.34 (1H, dd, J=4.5 Hz, 8.4 Hz), 4.54 (1H, ddd, J=4.5 Hz, 13.8 Hz,13.8 Hz), 4.91 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz),6.64 (1H, d, J=7.8 Hz), 6.88-6.93 (1H, m), 7.08-7.45 (6H, m).

Example 537

Compound 537 was synthesized by the same procedure as that of Example536.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz),1.46-1.57 (1H, m), 1.68-1.79 (1H, m), 1.98 (6H, s), 2.04-2.11 (1H, m),2.27-2.41 (1H, m), 2.72-2.94 (2H, m), 3.55-3.64 (1H, m), 3.91-4.00 (1H,m), 4.29-4.44 (2H, m), 5.10 (1H, s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H,d, J=7.8 Hz), 6.86-6.90 (1H, m), 7.05-7.24 (4H, m), 7.33 (2H, d, J=4.2Hz), 7.40 (1H, d, J=7.5 Hz).

Example 538

Compound 538 was synthesized by the same procedure as that of Example536.

¹H-NMR (DMSO-d₆) δ: 0.75 (6H, t, J=6.6 Hz), 1.28 (3H, d, J=6.6 Hz), 1.41(3H, d, J=6.6 Hz), 1.45-1.56 (1H, m), 1.67-1.78 (1H, m), 2.22-2.49 (4H,m), 2.74-2.97 (2H, m), 3.94-4.03 (1H, m), 4.29-4.41 (2H, m), 5.11 (1H,s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=6.9 Hz), 6.87 (1H, t, J=7.2Hz), 7.06-7.25 (4H, m), 7.33 (2H, d, J=7.2 Hz), 7.35 (1H, m).

Example 539

Compound 539 was synthesized by the same procedure as that of Example536.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.6 Hz),1.42-1.51 (2H, m), 1.75-1.91 (2H, m), 2.62-2.67 (1H, m), 2.65 (6H, s),2.74-2.97 (3H, m), 3.57-3.63 (1H, m), 3.91-3.26 (4H, m), 5.16 (1H, s),5.73 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=7.2 Hz), 6.89 (1H, t, J=6.9 Hz),7.12-7.28 (4H, m), 7.33-7.45 (3H, m).

Example 540

Compound 540 was synthesized by the same procedure as that of Example536.

¹H-NMR (CDCl₃) δ: 1.58-1.78 (2H, m), 2.06 (6H, s), 2.15-2.35 (2H, m),2.84-2.93 (1H, m), 2.96-3.11 (1H, m), 3.00 (3H, s), 3.65-3.74 (1H, m),3.99-4.14 (1H, m), 4.28-4.33 (1H, m), 4.94 (1H, s), 5.78 (1H, d, J=7.5Hz), 6.56 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=7.2 Hz), 6.95 (t, J=7.2 Hz),7.13-7.38 (6H, m).

Example 541

Compound 541 was synthesized by the same procedure as that of Example536.

¹H-NMR (CDCl₃) δ: 0.846 (6H, t, J=7.2 Hz), 1.49-1.75 (2H, m), 2.30-2.41(5H, m), 2.43-2.53 (1H, m), 2.85-2.93 (1H, m), 2.98-3.08 (1H, m), 3.01(3H, s), 3.63-3.74 (1H, m), 3.97-4.07 (1H, m), 4.30 (1H, dd, J=5.1 Hz,8.1 Hz), 4.95 (1H, s), 5.77 (1H, d, J=6.0 Hz), 6.56 (1H, d, J=7.8 Hz),6.65 (1H, d, J=7.8 Hz), 6.95 (1H, t, J=6.3 Hz), 7.13-7.38 (6H, m).

Example 542

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and triethylamine (20.5 mg, 0.202 mmol) was cooled to 1 to 3° C., andacetic acid anhydride (10.3 mg, 0.101 mmol) was added while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, water was added, and the mixture wasextracted with ethyl acetate three times. The combined extracts werewashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 15 mg of compound 542 as a solid.

¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.00(3H, s), 2.78-2.94 (2H, m), 3.04 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz),3.48-3.60 (1H, m), 3.98-3.07 (1H, m), 4.36 (1H, ddd, J=4.2 Hz, 13.5 Hz,13.5 Hz), 4.64 (1H, dd, J=3.9 Hz, 9.3 Hz), 4.87 (1H, s), 5.43 (1H, d,J=7.5 Hz), 6.57 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 6.85 (1H, t,J=6.0 Hz), 7.09-7.36 (6H, m), 7.41 (1H, brs).

Example 543

Compound 543 was synthesized by the same procedure as that of Example542.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, d, J=6.9 Hz), 2.79(1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz), 3.01 (1H, ddd, J=3.9 Hz, 13.5 Hz,13.5 Hz), 3.18-3.28 (1H, m), 3.46-3.59 (2H, m), 4.04-4.18 (1H, m), 4.27(1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 4.69 (1H, dd, J=3.3 Hz, 9.9 Hz),4.87 (0.9H, s), 5.17 (0.1H, s), 5.37 (0.9H, d, J=7.8 Hz), 4.50 (0.1H, d,J=7.8H), 6.32 (0.1H, d, J=7.8 Hz), 6.54 (1H, d, J=7.5 Hz), 6.78 (0.9H,d, J=7.5 Hz), 6.84 (1H, t, J=6.6 Hz), 6.91 (0.1H, d, J=6.0 Hz),7.06-7.51 (6H, m), 9.29 (1H, brs).

Example 544

Compound 544 was synthesized by the same procedure as that of Example542.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.46 (3H, d, J=6.3 Hz), 2.78(1H, ddd, J=4.5 Hz, 4.5 Hz, 15.9 Hz), 2.94-3.10 (2H, m), 3.19-3.54 (2H,m), 3.64 (3H, s), 3.96-3.11 (1H, m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz,13.5 Hz), 4.57 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.91 (1H, s), 5.57 (1H, brs),5.70 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.8 Hz),6.89 (1H, t, J=7.2 Hz), 7.08-7.47 (6H, m).

Example 545

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and pyridine (16 mg, 0.203 mmol) was cooled to 1 to 3° C., and2-methoxyacetyl chloride (11 mg, 0.101 mmol) was added while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, water was added, and the mixture wasextracted with ethyl acetate three times. The combined extracts werewashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 22 mg of compound 545 as a solid.

¹H-NMR (CDCl₃) δ: 1.31 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz), 2.77(1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 2.99-3.11 (2H, m), 3.47 (3H, s),3.47-3.55 (1H, m), 3.64-3.72 (1H, m), 3.77-3.88 (2H, m), 4.02-4.11 (1H,m), 4.23 (1H, ddd, J=4.2 Hz, 13, 8 Hz, 13.8 Hz), 4.47 (1H, dd, J=3.3 Hz,9.9 Hz), 4.94 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=9.0 Hz),6.67 (1H, 7.8 Hz), 6.80 (1H, brt), 6.91 (1H, t, J=7.5 Hz), 7.08-7.23(5H, m), 7.29-7.36 (1H, m).

Example 546

First Step

To a dimethylformamide (1 ml) solution of 2-(methylthio)acetic acid(15.7 mg, 0.148 mmol) were added EDCI (28.5 mg, 0.148 mmol) and1-hydroxy benzotriazole (11.4 mg, 0.0742 mmol) at room temperature, themixture was stirred at the same temperature for 5 minutes, and compound532 was added. The reaction solution was stirred at room temperature for1 hour, and diluted with methanol (3 ml). The solution was cooled to 1to 30C, a 2N aqueous sodium hydroxide solution (1 ml) was added, themixture was stirred at the same temperature for 30 minutes, and themixture was neutralized with 2N hydrochloric acid (1 ml). The reactionsolution was extracted with ethyl acetate three times, the combinedextracts were washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was washedwith ethyl acetate-diisopropyl ether to obtain 15 mg of compound 546 asa solid.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, J=6.6 Hz), 2.11 (3,s), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.1 Hz), 2.99-3.16 (4H, m), 3.50(1H, ddd, J=4.5 Hz, 4.5 Hz, 12.9 Hz), 3.68 (1H, d, J=10.2 Hz), 3.97-4.11(1H, m), 4.26 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.94 (3H, s), 5.69(1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.8 Hz), 6.90(1H, t, J=6.0 Hz), 7.09 (1H, d, J=7.5 Hz), 7.20-7.25 (3H, m), 7.29-7.36(1H, m), 7.36-7.49 (1H, m).

Example 547

First Step

To an acetic acid (3 ml) solution of compound 547A (367 mg, 0.812 mmol)synthesized by the same procedure as that of Example 516 anddibenzosuberol (205 mg, 0.974 mmol) was added dropwise sulfuric acid(0.6 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and extracted with ethyl acetate three times. The extract waswashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was dissolved in methanol(3 ml), a 2N aqueous sodium hydroxide solution (1 ml) was added at roomtemperature, and the mixture was stirred for 30 minutes. The reactionsolution was neutralized with 2N hydrochloric acid (1 ml), and extractedwith ethyl acetate three times. The combined extracts were dried withsodium sulfate, and the solvent was distilled off. The resulting crudeproduct was washed with ethyl acetate-diisopropyl ether to obtain 75 mgof compound 547 as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.9 Hz), 1.45 (3H, d, J=6.3 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd,J=3.9 Hz, 3, 9 Hz, 17.7 Hz), 3.64 (1H, dd, J=6.9 Hz), 12.3 Hz), 3.82(1H, dd, J=3.3 Hz, 12.3 Hz), 3.86-3.97 (1H, m), 4.34-4.44 (2H, m), 4.88(1H, s), 5.35 (1H, d, J=7.5 Hz), 6.52-6.58 (2H, m), 6.82 (1H, dt, J=1.8Hz, 7.2 Hz), 7.06-7.35 (6H, m).

Example 548

Compound 548 was synthesized by the same procedure as that of Example547.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.6 Hz), 1.50 (3H, d, J=6.6 Hz),1.70-1.81 (1H, m), 1.88-2.00 (1H, m), 2.85 (1H, ddd, J=4.5 Hz, 4.5 Hz,14.1 Hz), 2.99-3.11 (1H, m), 3.48-3.57 (1H, m), 3.68-3.73 (2H, m),3.83-3.92 (1H, m), 4.3.0 (1H, ddd, J=4.2 Hz, 13.8 Hz, 13.8 Hz), 4.54(1H, dd, J=3.6 Hz, 11.1 Hz), 4.67 (1H, s), 5.69 (1H, d, J=7.8 Hz), 6.62(1H, d, J=7.5 Hz), 6.64 (1H, d, J=5.7 Hz), 6.90 (1H, t, J=6.9 Hz),7.07-7.36 (6H, m).

Example 549

First Step

To an acetic acid (3 ml) solution of compound 549A (997 mg, 1.69 mmol)synthesized by the same procedure as that of Example 516 anddibenzosuberol (1.07 g, 5.08 mmol) was added dropwise sulfuric acid (0.6ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and extracted with ethyl acetate three times. The extract waswashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 513 mg of compound 549B.

¹H-NMR (CDCl₃) δ: 2.09 (3H, s), 2.71 (1H, ddd, J=3.6 Hz, 13.5 Hz, 13.5Hz), 3.18-3.27 (1H, m), 3.42-3.56 (2H, m), 3.80 (1H, dd, J=2.7 Hz, 14.1Hz), 4.03 (1H, dd, J=10.2 Hz, 14.1 Hz), 4.15 (1H, ddd, J=4.2 Hz, 4.2 Hz,9.3 Hz), 4.32-4.40 (1H, m), 4.49-4.53 (2H, m), 4.94 (1H, s), 5/83 (1H,d, J=7.8 Hz), 6.63 (1H, d, J=7.5 Hz), 6.69 (1H, d, J=7.8 Hz), 6.76 (1H,d, J=6.6 Hz), 6.91 (1H, t, J=7.5 Hz), 7.00 (1H, d, J=8.1 Hz), 7.12-7.17(2H, m), 7.20-7.32 (2H, m), 7.82-7.89 (4H, m).

Second Step

To a methanol (5 ml) solution of compound 549B (513 mg, 0.829 mmol) wasadded hydrazine hydrate (124.5 mg, 2.49 mmol), and the mixture wasrefluxed for 2 hours. After cooled to room temperature, to the reactionsolution were added 2N hydrochloric acid (30 ml) and ethyl acetate (30ml). After the layers were separated, the organic layer was extractedwith 2N hydrochloric acid two times. The combined aqueous layers wereneutralized with sodium bicarbonate water, and extracted withchloroform-methanol three times. The combined organic layers were driedwith sodium sulfate, and the solvent was distilled off. The resultingcrude product was washed with ethyl acetate-diisopropyl ether to obtain135 mg of compound 549.

¹H-NMR (DMSO-d₆) δ: 2.40-2.50 (1H, m), 2.72-2.80 (1H, m), 2.83-2.98 (2H,m), 3.03-3.66 (4H, m), 3.79-3.87 (1H, m), 4.11 (1H, 4.2 Hz), 4.32-4.44(1H, m), 5.12 (1H, s), 5.51 (1H, 7.5 Hz), 6.69 (d, J=7.5 Hz), 6.84-6.90(1H, m), 7.07-7.24 (4H, m), 7.30-7.34 (2H, m), 7.39-7.42 (1H, m).

EXAMPLE

According to Example 536, compound 550 was synthesized from compound 549by the same procedure.

¹H-NMR (DMSO-d₆) δ: 0.77 (6H, t, 6.9 Hz), 1.99-2.36 (3H, m), 2.38-2.56(1H, m), 2.64 (1H, dd, J=3.9 Hz, 14.1 Hz), 2.75 z81H, ddd, J=4.5 Hz, 4.5Hz, 14.4 Hz), 2.89-3.00 (1H, m), 3.09-3.68 (4H, m), 3.74-3.82 (1H, m),4.09 (1H, brs), 4.17 (1H, dd, J=3.6 Hz, 8.4 Hz), 5.03 (1H, brs), 5.17(1H, s), 5.53 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz), 6.84 (1H, d,J=7.8 Hz), 6.91 (1H, t, J=7.2 Hz), 7.12-7.26 (4H, m), 7.31-7.44 (4H, m),7.45 (1H, d, J=7.2 Hz).

Example 551

According to Example 536, compound 551 was synthesized from compound 549by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.99 (6H, s), 2.27 (1H, brs), 2.51-2.27 (3H, m),3.56-3.70 (4H, m), 4.03 (2H, brs), 4.36 (1H, brs), 4.94 (2H, brs), 5.29(1H, brs), 6.54-6.83 (3H, m), 7.11-7.33 (6H, m).

Example 552

First Step

To an acetic acid (2 ml) solution of compound 552A (137 mg, 0.367 mmol)synthesized by the same procedure as that of Example 516 anddibenzosuberol (386 mg, 1.83 mmol) was added dropwise sulfuric acid (0.4ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and extracted with ethyl acetate three times. The extract waswashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was dissolved in methanol(5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at roomtemperature, and the mixture was stirred for 30 minutes. The reactionsolution was neutralized with 2N hydrochloric acid (2 ml), and extractedwith ethyl acetate two times. The combined extracts were dried withsodium sulfate, and the solvent was distilled off. The resulting crudeproduct was washed with ethyl acetate to obtain 62 mg of compound 552.

¹H-NMR (CDCl₃) δ: 1.71-1.82 (1H, m), 2.09-2.21 (1H, m), 2.82-2.90 (1H,m), 3.06 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.22-3.43(3H, m), 3.60 (1H, ddd, J=10.5 Hz, 10.5 Hz, 17.4 Hz), 3.79-3.96 (3H, m),4.12-4.21 (1H, m), 4.46 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.98 (1H, s), 5.89(1H, d, J=7.5 Hz), 6.62 (1H, d, J=6.9 Hz), 6.64 (1H, d, J=7.5 Hz),6.88-6.93 (1H, m), 7.11-7.37 (6H, m).

Example 553

Compound 553 was synthesized by the same procedure as that of Example552.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.9 Hz),1.94-2.00 (1H, m), 2.82-2.90 (1H, m), 3.00-3.11 (1H, m), 5.31-3.59 (2H,m), 3.64-3.74 (1H, m), 3.94-4.04 (3H, m), 4.25-4.36 (1H, m), 5.04 (1H,s), 5.87 (1H, d, J=7.2 Hz), 6.65 (1H, d, J=7.2 Hz), 7.12 (1H, d, J=7.5Hz), 6.92 (1H, t, J=8.1 Hz), 7.10 (1H, d, J=7.2 Hz), 7.15-7.38 (5H, m).

Example 554

First Step

To an acetic acid (2 ml) solution of compound 554A (100 mg, 0.177 mmol)synthesized by the same procedure as that of Example 516 anddibenzosuberol (186 mg, 0.885 mmol) was added dropwise sulfuric acid(0.4 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and extracted with ethyl acetate three times. The extract waswashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was dissolved in methanol(5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at roomtemperature, and the mixture was stirred for 30 minutes. The reactionsolution was neutralized with an aqueous citric acid solution, andextracted with ethyl acetate two times. The combined extracts werewashed with sodium bicarbonate water, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was washedwith ethyl acetate to obtain 24 mg of compound 554.

¹H-NMR (CDCl₃) δ: 2.81-2.91 (2H, m), 2.98-3.09 (1H, m), 3.60-3.75 (2H,m), 3.91-4.04 (2H, m), 4.08-4.17 (2H, m), 4.22-4.33 (2H, m), 4.80 (1H,s), 5.69 (1H, d, J=7.8 Hz), 6.48 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.5Hz), 6.80-6.85 (1H, m), 7.13-7.35 (6H, m).

Example 555

To an acetic acid (4 ml) solution of compound 555A (380 mg, 1.11 mmol)synthesized according to Example 516 and dibenzosuberol (1.16 g, 5.52mmol) was added dropwise sulfuric acid (0.8 ml) at room temperature, andthe mixture was stirred at the same temperature for 30 minutes. Thereaction solution was diluted with water, and extracted with ethylacetate three times. The extract was washed with water once, and driedwith sodium sulfate, and the solvent was distilled off. The resultingcrude product was dissolved in methanol (5 ml), a 2N aqueous sodiumhydroxide solution (2 ml) was added at room temperature, and the mixturewas stirred for 30 minutes. The reaction solution was neutralized withan aqueous citric acid solution, and extracted with ethyl acetate threetimes. The combined extracts were dried with sodium sulfate, and thesolvent was distilled off. To the resulting crude product were addedethyl acetate-diisopropyl ether, and the precipitated residue wasfiltered to obtain 22 mg of compound 555.

¹H-NMR (CDCl₃) δ: 1.62 (3H, d, J=6.9 Hz), 2.81 (1H, ddd, J=4.2 Hz, 4.2Hz, 14.4 Hz), 3.09 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 3.37 (3H, s),3.37-3.53 (2H, m), 3.70 (1H, d, J=5.4 Hz), 4.23-4.30 (2H, m), 4.33-4.44(1H, m), 4.94 (1H, s), 5.70 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz),6.64 (1H, d, J=7.8 Hz), 6.88-6.92 (1H, m), 7.08-7.37 (6H, m).

Example 556

Compound 556 was synthesized by the same procedures as those of Example65 and Example 516.

¹H-NMR (CDCl₃) δ: 1.66-1.78 (2H, m), 1.97 (3H, s), 2.19-2.31 (1H, m),2.35-2.44 (1H, m), 2.49-2.57 (1H, m), 2.85-2.93 (1H, m), 3.06 (1H, J=3.9Hz, 12.9 Hz, 12.9 Hz), 3.27-3.39 (2H, m), 3.34 (3H, s), 3.58-3.73 (3H,m), 3.96-4.04 (1H, m), 4.08-4.18 (1H, m), 4.60 (1H, dd, J=3.0 Hz, 11.1Hz), 4.96 (1H, s), 6.52 (1H, d, J=7.5 Hz), 6.87-6.92 (1H, m), 7.18-7.28(4H, m), 7.31-7.40 (2H, m), 7.65 (1H, s), 12.04 (1H, s), 14.33 (1H, s).

Example 557

Compound 557 was synthesized by the same procedure as that of Example149.

MS: m/z=419 [M+H]⁺.

Example 558

To a DMSO (2 mL) solution of compound 63B (68.8 mg, 0.120 mmol) wasadded copper chloride (39.2 mg, 0.396 mmol), and the mixture was stirredat 110 degree for 2 hours and, further, at 120 degree for 1 hour.Thereafter, copper chloride (50.0 mg, 0.505 mmol) was added, and themixture was stirred at 200 degree for 1 hour. The reaction solution waspurified using a LCMS fractionating device, the eluted solvent wasdistilled off, to the concentrated residue was added diethyl ether, andthe precipitated white solid was filtered. Washing with diethyl ether,and drying afforded 20.9 mg of compound 558.

MS: m/z=439 [M+H]⁺.

Example 559

First Step

Compound 48A (43 mg, 0.083 mmol) was dissolved in dichloromethane (6.0mL), manganese dioxide (120 mg, 1.38 mmol) was added, and the mixturewas stirred at room temperature for 3 hours. After the reaction solutionwas filtered with celite, the filtrate was concentrated to obtain 22.3mg of compound 559B as a pale yellow solid.

¹HNMR (CDCl₃) δ: 3.17 (3H, s), 3.41-3.55 (4H, m), 3.95-4.07 (2H, m),4.28 (1H, d, J=16.1 Hz), 4.53 (1H, d, J=11.8 Hz), 5.49 (2H, d, J=2.0Hz), 6.97-7.66 (16H, m), 10.07 (1H, s).

Second Step

Compound 559B (22 mg, 0.043 mmol) was dissolved in THF (6.0 mL), a 40%methanamine methanol solution (6.5 ul, 0.064 mmol) and acetic acid (3.7ul, 0.064 mmol) were added, and the mixture was stirred at roomtemperature for 5 minutes. The reaction solution was ice-cooled,NaBH(OAc)₃ (14 mg, 0.064 mmol) was added, and the mixture was stirred atroom temperature overnight. To the reaction solution were added waterand chloroform, and the chloroform layer was separated. The aqueouslayer was extracted with chloroform, and sodium sulfate was added to thecombined extracts to dry them. The solvent was distilled off to obtain24 mg of compound 559C as a pale yellow solid.

MS: m/z=538 [M+H]⁺.

Third Step

Compound 559 was synthesized by the same procedure as that of Example 1.

MS: m/z=448 [M+H]⁺.

Example 560

First Step

A dioxane (20 mL) mixed solution of (methoxymethyl)triphenylphosphoniumchloride (6.73 g, 19.0 mmol) was cooled to 0° C., and a 1.06M NaHMDStoluene solution (18.0 ml, 19.0 mmol) was added dropwise while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, compound 383A was added, and themixture was refluxed for 1 hour and 30 minutes. The reaction solutionwas returned to room temperature, and water and ethyl acetate wereadded. The ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. To the combined extracts was added sodiumsulfate to dry them. The solvent was distilled off, and the resultingoil was purified by silica gel column chromatography, and eluted withn-hexane-ethyl acetate (95:5, v/v). Concentration of an objectivefraction afforded 2.22 g of compound 560B as an oil.

¹H-NMR (CDCl₃) δ: 3.68 (3H, s), 3.73 (3H, s), 4.20 (4H, brs), 6.17 (1H,s), 6.39 (1H, s), 6.96-7.07 (6H, m), 7.18-7.32 (9H, m), 7.32-7.46 (1H,m).

Second Step

Compound 560B (1.98 g, 7.78 mmol) was dissolved in dichloromethane (30mL), a 70% aqueous perchloric acid solution (8.0 ml, 93 mmol) was added,and the mixture was stirred at room temperature overnight. To thereaction solution was added an aqueous saturated sodium carbonatesolution, and the dichloromethane layer was separated. The aqueous layerwas extracted with dichloromethane, and magnesium sulfate was added tothe combined extracts to dry them. The solvent was distilled off, andthe resulting oil was purified by silica gel column chromatography, andeluted with n-hexane-ethyl acetate (90:10, v/v). Concentration of anobjective fraction afforded 1.80 g of compound 560C as an oil.

¹H-NMR (CDCl₃) δ: 3.93 (1H, d, J=16.1 Hz), 4.06 (1H, d, J=16.1 Hz), 4.53(1H, s), 7.11-7.50 (8H, m), 9.89 (1H, s).

MS: m/z=241 [M+H]⁺.

Third Step

To a dichloromethane (30 mL) solution of compound 560C (2.87 g, 11.9mmol) were added tetraisopropoxytitanium (17.5 mL, 59.7 mmol) and(S)-4-methylbenzenesulfinamide (2.27 g, 14.3 mmol) at room temperature,then the mixture was refluxed for 3 hours and 30 minutes. The reactionsolution was ice-cooled, ice water (30 ml) was added, the mixture wasstirred for 1 hour while temperature was retained at the sametemperature, and the precipitated solid was filtered using celite. Theresulting filtrate was extracted with dichloromethane, and magnesiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (70:30, v/v).Concentration of an objective fraction afforded 3.16 g of compound 560Das a yellow solid.

¹H-NMR (CDCl₃) δ: 2.39 (6H, s), 3.60 (1H, d, J=15.2 Hz), 3.68 (1H, d,J=14.9 Hz), 3.97 (1H, d, J=15.0 Hz), 4.07 (1H, d, J=15.0 Hz), 4.90 (1H,d, J=2.7 Hz), 4.92 (1H, d, J=2.9 Hz), 7.08-7.26 (20H, m), 7.46-7.51 (4H,m), 8.62 (1H, d, J=2.8 Hz), 8.65 (1H, d, J=2.7 Hz).

MS: m/z=378 [M+H]⁺.

Fourth Step

A THF (30 mL) suspension of a 1M cyanodiethylaluminum toluene solution(16.7 mL, 16.7 mmol) was cooled to 0 degree, 2-propanol (1.29 mL, 16.7mmol) was added and, thereafter, the mixture was stirred for 1 hourwhile temperature was retained at the same temperature. Thereafter, thereaction solution was cooled to −60 degree, a THF (12 mL) solution ofcompound 560D (3.16 g, 8.37 mmol) was added dropwise, the mixture wasstirred for 15 minutes while temperature was retained at the sametemperature, thereafter, temperature was raised to room temperature, andthe mixture was stirred overnight. The reaction solution was ice-cooled,an aqueous saturated ammonium chloride solution was added, the mixturewas stirred at room temperature for 1 hour and 30 minutes and,thereafter, the precipitated solid was filtered using celite, and washedwith dichloromethane. The dichloromethane layer of the filtrate wasseparated, and the aqueous layer was extracted with dichloromethane and,thereafter, sodium sulfate was added to the combined extracts to drythem. The solvent was distilled off, and the resulting oil was purifiedby silica gel column chromatography, and eluted with chloroform-methanol(97:3, v/v). Concentration of an objective fraction afforded 1.88 g ofcompound 560E.

MS: m/z=427 [M+Na]⁺.

Fifth Step

A methanol (4 mL) solution of compound 560E (235 mg, 0.581 mmol) wascooled to 0 degree, cobalt (II) chloride hexahydrate (55.3 mg, 0.232mmol) was added, and the mixture was stirred at room temperature for 30minutes. Thereafter, the reaction solution was ice-cooled, a DMF (4 mL)solution of sodium borohydride (88 mg, 2.3 mmol) was added dropwise, andthe mixture was stirred at the same temperature for 5 minutes, and atroom temperature for 1 hour. Then, Boc₂O (0.674 mL, 2.90 mmol) wasadded, and the mixture was stirred for 30 minutes. To the reactionsolution was added water, the mixture was extracted with ethyl acetate,and sodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol (98:2,v/v). Concentration of an objective fraction afforded a crude product(211 mg) of compound 560F.

MS: m/z=509 [M+Na]⁺.

Sixth Step

To a methanol (6 mL) solution of the crude product (211 mg) of compound560F was added TFA (0.128 mL, 1.66 mmol), and the mixture was stirred atroom temperature for 2.5 hours. To the reaction solution was addedtriethylamine (0.230 mL, 1.66 mmol), the solvent was distilled off, andthe resulting crude product of compound 560G was used in a next reactionwithout purification.

MS: m/z=371 [M+H]⁺.

Seventh Step

To a toluene (4 mL) solution of the crude product of compound 560G wasadded dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (132 mg,0.416 mmol), and the mixture was refluxed for 1 hour and 30 minutes. Thereaction solution was subjected to silica gel column chromatography, andeluted with chloroform-methanol (100:0→90:10, v/v). Concentration of anobjective fraction afforded a crude product (287 mg) of compound 560H.

MS: m/z=671 [M+H]⁺.

Eighth Step

To the crude product of compound 560H obtained in the seventh step wasadded a 4N hydrochloric acid ethyl acetate solution (3 mL), and themixture was stirred at room temperature for 30 minutes. The solvent wasdistilled off, to the resulting concentrated residue were added THF (2mL) and an aqueous saturated sodium bicarbonate solution (2 mL), and themixture was stirred at room temperature for 45 minutes. To the reactionsolution was added water, the mixture was extracted with chloroform, andsodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol(100:0→94:6, v/v). Concentration of an objective fraction afforded 27 mgof compound 560I as a yellow solid.

MS: m/z=539 [M+H]⁺.

Ninth Step

Compound 560I (27 mg, 0.050 mmol) was dissolved in DMF (2 mL), cesiumcarbonate (82 mg, 0.25 mmol) and methyl iodide (0.010 mL, 0.16 mmol)were added, and the mixture was stirred at room temperature for 1 hourand 30 minutes. To the reaction solution was added water, the mixturewas extracted with ethyl acetate, and sodium sulfate was added to thecombined extracts to dry them. The solvent was distilled off, and theresulting oil was subjected to silica gel column chromatography, andeluted with chloroform-methanol (100:0→94:6, v/v). Concentration of anobjective fraction afforded a crude product of compound 560J.

MS: m/z=553 [M+H]⁺.

Tenth Step

To an EtOH (2 mL) solution of the crude product of compound 560Jobtained in the ninth step was added 2N NaOH (1 mL), and the mixture wasstirred at room temperature for 40 minutes. To the reaction solution wasadded a 2N aqueous HCl solution, the mixture was extracted with ethylacetate, and sodium sulfate was added to the combined extracts to drythem. The solvent was distilled off to obtain 17 mg of compound 560K asa white oil.

MS: m/z=539 [M+H]⁺.

Eleventh Step

To compound 560K (17 mg, 0.032 mmol) was added TFA (2.0 mL), and themixture was stirred at room temperature for 35 minutes. The reactionsolution was subjected to toluene azeotropy, to the resultingconcentrated residue was added isopropyl ether, and the precipitatedsolid was filtered and washed to obtain 7.1 mg of compound 560 as a pinksolid.

MS: m/z=449 [M+H]⁺.

Example 561

First Step

To a crude product (433 mg) of compound 560H was added a 4N hydrochloricacid ethyl acetate solution (3 mL), and the mixture was stirred at roomtemperature for 1 hour. The solvent was distilled off, to a THF (2 mL)solution of the resulting residue was added acetone (2 mL), the mixturewas stirred at room temperature for 20 minutes, NaBH(OAc)₃ (70 mg, 0.32mmol) was added, and the mixture was stirred at room temperature for 1hour and 30 minutes. Thereafter, to the reaction solution was added anaqueous saturated sodium bicarbonate solution (3 mL), and the mixturewas stirred at room temperature overnight. To the reaction solution wasadded water, the mixture was extracted with chloroform, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→94:6, v/v).Concentration of an objective fraction afforded a crude product (79 mg)of compound 561A.

MS: m/z=581 [M+H]⁺.

Second Step

To an EtOH (4 mL) solution of the crude product (79 mg) of compound 561Awas added 2N NaOH (2 mL), and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added a 2N aqueousHCl solution, the mixture was extracted with ethyl acetate, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→94:6, v/v).Concentration of an objective fraction afforded compound 561B (53 mg).

MS: m/z=567 [M+H]⁺.

Third Step

A DMF (2 mL) solution of compound 561B (53 mg, 0.093 mmol) was cooled to0 degree, triethylamine (0.039 mL, 0.28 mmol) and ethyl chloroformate(0.018 mL, 0.187 mmol) were added, and the mixture was stirred at roomtemperature for 10 minutes. Thereafter, the reaction solution was cooledto 0 degree, sodium azide (18 mg, 0.28 mmol) was added, and the mixturewas stirred for 50 minutes while temperature was retained at the sametemperature. To the reaction solution was added water, the mixture wasextracted with dichloromethane, and the combined extracts wereconcentrated to obtain a crude product of compound 561C.

MS: m/z=592 [M+H]⁺.

Fourth Step

The crude product (55 mg) of compound 561C was dissolved in methanol (2mL), and the mixture was stirred at 50° C. for 1 hour. The reactionsolution was subjected to silica gel column chromatography, and elutedwith chloroform-methanol (100:0→94:6, v/v). Concentration of anobjective fraction afforded a crude product (43 mg) of compound 561D.

MS: m/z=596 [M+H]⁺.

Fifth Step

To an EtOH (2 mL) solution of the crude product (43 mg) of compound 561Dwas added 2N NaOH (4 mL), and the mixture was stirred at 60 degree for 1hour. The solvent was distilled off, water was added, the mixture wasextracted with ethyl acetate and, thereafter, sodium sulfate was addedto the combined extracts to dry them. The solvent was distilled off, theresulting oil was subjected to amino column chromatography, and elutedwith chloroform-methanol (100:0→80:20, v/v). Concentration of anobjective fraction afforded 16 mg of compound 561E as a pale yellowsolid.

MS: m/z=538 [M+H]⁺.

Sixth Step

Compound 561E (16 mg, 0.029 mmol) was dissolved in EtOH (1 mL) and a 48%aqueous tetrafluoroboric acid (1 mL), the reaction solution was cooledto 0 degree, sodium nitrite (15 mg, 0.22 mmol) was added, and themixture was stirred for 1 hour and 30 minutes while temperature wasretained at the same temperature and, further, at room temperature for 2hours and 30 minutes. To the reaction solution was added water, themixture was extracted with chloroform, and sodium sulfate was added tothe combined extracts to dry them. The solvent was distilled off, to theresulting concentrated residue were added ethyl acetate and isopropylether, and the precipitated solid was filtered and washed to obtain 5 mgof compound 561 as a white solid.

¹H-NMR (CDCl₃) δ: 0.96 (3H, d, J=6.9 Hz), 1.17 (3H, d, J=6.8 Hz), 3.37(1H, d, J=13.3 Hz), 3.88 (1H, dd, J=13.4, 4.3 Hz), 3.99 (1H, d, J=14.9Hz), 4.08 (1H, d, J=11.3 Hz), 4.52 (1H, d, J=14.9 Hz), 4.81-4.90 (1H,m), 5.67 (1H, dd, J=11.3, 3.1 Hz), 5.94 (1H, d, J=7.4 Hz), 6.59 (1H, d,J=6.4 Hz), 6.72 (1H, d, J=7.3 Hz), 6.86 (1H, t, J=7.1 Hz), 7.09 (1H, t,J=7.6 Hz), 7.16-7.31 (5H, m).

Example 562

Compound 562 was synthesized by the same procedure as that of Example561.

¹H-NMR (CDCl₃) δ: 3.07 (3H, s), 3.21 (1H, d, J=12.3 Hz), 4.00-4.31 (4H,m), 5.78 (1H, d, J=10.5 Hz), 5.94 (1H, d, J=7.4 Hz), 6.54 (1H, d, J=7.3Hz), 6.69 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=7.6 Hz), 7.14-7.41 (6H, m).

MS: m/z=405 [M+H]⁺.

Example 563

First Step

Compound 563A (Tetrahedron Letters, 34, 953-956, 1993, 41.1 g, 154 mmol)was dissolved in THF (300 mL), 1M BH₃-THF (770 mL) was slowly added atroom temperature, and the mixture was stirred for 18 hours. 3Nhydrochloric acid (513 mL) was slowly added, and the mixture wasrefluxed for 1 hour, and was progressed to a next step withoutpurification.

LC-MS: m/z=254 [M+H]⁺.

Second Step

Using a solution containing compound 563B, according to Example 12,compound 563C was synthesized.

LC-MS: m/z=353 [M+H]⁺.

¹H-NMR (DMSO-d₆): 1.40 (9H, s), 2.65-2.72 (1H, m), 2.86-2.92 (3H, m),3.47-3.56 (3H, m), 3.56-3.69 (1H, m), 6.63 (1H, s), 7.11-7.26 (8H, m).

Third Step

A toluene (30 mL) solution of compound 563C (2.16 g, 6.79 mmol) anddimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (2.38 g, 6.75mmol) was stirred at 100° C. for 4 hours. The reaction solution wasdistilled off under reduced pressure, and the resulting crude product ofcompound 563D was used in a next reaction without purification.

MS: m/z=653.05 [M+H]⁺.

Fourth Step

To an ethyl acetate (20 mL) solution of the crude product of compound563D was added hydrogen chloride (4N ethyl acetate solution, 20 mL) atroom temperature, and the mixture was stirred for 30 minutes. Thereaction solution was distilled off under reduced pressure, and theresulting crude product of compound 563E was used in a next reactionwithout purification.

MS: m/z=553.05 [M+H]⁺.

Fifth Step

To a tetrahydrofuran (40 mL) solution of the crude product of compound563E was added saturated sodium bicarbonate water (5 mL) at roomtemperature, and the mixture was stirred for 16 hours. To the reactionsolution was added water (50 mL), the mixture was extracted withchloroform three times, and the extracts were combined, and dried withsodium sulfate. The solvent was distilled off under reduced pressure,and diethyl ether and chloroform were added to the resulting residue tocovert them into a powder, to obtain compound 563F (2.90 g, 70.2%) as awhite solid.

MS: m/z=521.05 [M+H]⁺.

Sixth Step

To a methanol (7.5 mL) suspension of compound 563F (523 mg, 1.01 mmol)was added an aqueous sodium hydroxide solution (2 M, 1.5 mL) at roomtemperature, and the mixture was stirred for 3 hours. To the reactionsolution were added hydrochloric acid (2N, 1.5 mL) and water (3 mL) atroom temperature and, thereafter, the mixture was stirred at 0° C. for15 minutes. The precipitated solid was filtered, and washed with waterand diethyl ether to obtain compound 563G (418 mg, 82.0%) as a whitesolid.

MS: m/z=507.00 [M+H]⁺.

Seventh Step

A diphenyl ether (5 mL) suspension of compound 563G (107 mg, 0.211 mmol)was stirred at 240° C. for 1 hour under microwave irradiation. Thereaction solution was purified by silica gel column chromatography(methanol/chloroform=0%→5%) to obtain compound 563H (64.4 mg, 65.9%) asa white solid.

MS: m/z=463.05 [M+H]⁺.

Eighth Step

A methanol (30 mL) solution of compound 563H (64.4 mg, 0.139 mmol) washydrogenated by passing through 10% Pd—C CatCart (H-cube, Full-H₂ mode,25° C.) for 3 hours. The reaction solution was distilled off underreduced pressure, and ethyl acetate and methanol were added to theresulting residue to convert it into a powder, to obtain compound 563(31.1 mg, 60.0%) as a gray white solid.

¹HNMR (DMSO-d₆) δ: 2.50-3.03 (3H, m), 3.50-3.72 (3H, m), 4.29 (1H, d,J=11.4 Hz), 5.12 (1H, m), 5.69 (1H, d, J=7.2 Hz), 6.50 (1H, d, J=7.7Hz), 6.75 (1H, d, J=7.7 Hz), 6.84 (1H, m), 7.14-7.30 (6H, m), 9.16 (1H,d, J=4.8 Hz).

MS: m/z=372.90 [M+H]⁺.

Example 564

First Step

To a dimethylformamide (2 mL) suspension of compound 563H (64.2 mg,0.139 mmol) and cesium carbonate (220 mg, 0.675 mmol) was added methyliodide (0.0430 mL, 0.688 mmol) at room temperature, and the mixture wasstirred for 3 hours. To the reaction solution was added water (10 mL) atroom temperature, and the mixture was extracted with ethyl acetate (30mL). The organic layer was washed with water (10 mL) and an aqueoussaturated sodium chloride solution (10 mL), and dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography(methanol/chloroform=2.5%→10%) to obtain compound 564A (56.0 mg, 85.0%)as a colorless gummy substance.

MS: m/z=477.00 [M+H]⁺.

Second Step

A solution of compound 564A (56.0 mg, 0.118 mmol) in methanol (10 mL),ethyl acetate (5 mL) and tetrahydrofran (5 mL) was hydrogenated bypassing through 10% Pd—C CatCart (H-cube, Full-H₂ mode, 250C) for 75minutes. The reaction solution was distilled off under reduced pressure,and ethyl acetate and methanol were added to the resulting residue toconvert it into a powder, to obtain compound 564 (22.0 mg, 48.4%) as agray white solid.

¹HNMR (DMSO-d₆) δ: 2.86-2.98 (6H, m), 3.51-3.58 (2H, m), 3.94 (1H, m),4.30 (1H, d, J=11.1 Hz), 5.19 (1H, d, J=10.2 Hz), 5.79 (1H, d, J=6.9Hz), 6.49 (1H, d, J=7.4 Hz), 6.74 (1H, d, J=7.4 Hz), 6.85 (1H, m), 7.14(2H, m), 7.25 (4H, m), 12.50 (1H, brs).

MS: m/z=387.05 [M+H]⁺.

Example 565

Compound 565 was synthesized by the same procedure as that of Example564.

MS: m/z=443.95 [M+H]⁺.

Example 566

First Step

A dimethylformamide (2 mL) suspension of compound 563H (75.4 mg, 0.163mmol), 3-iodobenzonitrile (124 mg, 0.541 mmol), copper (I) iodide (33.2mg, 0.174 mmol), potassium carbonate (74.7 mg, 0.540 mmol) andN,N′-dimethylethylenediamine (0.0200 ml, 0.186 mmol) was stirred at 140°C. for 2 hours under microwave irradiation. To the reaction solutionwere added water (10 mL) and hydrochloric acid (2M, 2 mL) at roomtemperature, and the mixture was extracted with ethyl acetate. Theextract was filtered with celite, and the filtrate was washed with water(10 mL×2) and an aqueous saturated sodium chloride solution (10 mL), anddried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product of compound 566A was used in anext reaction without purification.

MS: m/z=564.05 [M+H]⁺.

Second Step

To a methylene chloride (10 mL) solution of the crude product ofcompound 566A obtained in the first step was added trifluoroacetic acid(2 mL) at room temperature, and the mixture was stirred for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresulting residue was purified by preparative LCMS to obtain compound566 (30.3 mg, 39.3%) as a yellow solid.

¹HNMR (DMSO-d₆) δ: 2.81-2.94 (2H, m), 3.38-3.58 (2H, m), 4.54 (1H, d,J=10.5 Hz), 4.64 (1H, d, J=10.5 Hz), 5.35 (1H, d, J=10.5 Hz), 5.76 (1H,m), 6.66-6.71 (3H, m), 6.90 (1H, m), 7.06-7.15 (6H, m), 7.76 (2H, m),7.90 (2H, m).

MS: m/z=473.90 [M+H]⁺.

Example 567

Compound 567 was synthesized by the same procedure as that of Example566.

¹HNMR (DMSO-d₆) δ: 2.80-3.00 (2H, m), 3.40-3.70 (2H, m), 4.52 (1H, m),4.64 (1H, m), 5.38 (1H, m), 5.76 (1H, m), 6.60-7.20 (10H, m), 7.60-7.90(3H, m), 8.11 (1H, m).

MS: m/z=474.00 [M+H]⁺.

Example 568

Compound 568 was synthesized by the same procedure as that of Example566.

¹HNMR (DMSO-d₆) δ: 2.87-2.96 (2H, m), 3.34-3.73 (2H, m), 4.64 (2H, m),5.33 (1H, m), 5.71 (1H, d, J=7.2 Hz), 6.61 (1H, d, J=7.8 Hz), 6.87-6.95(3H, m), 7.00-7.27 (6H, m), 7.62 (2H, m), 7.86 (1H, m), 8.07 (1H, m).

MS: m/z=474.00 [M+H]⁺.

Example 569

Compound 569 was synthesized by the same procedure as that of Example566.

MS: m/z=449.95 [M+H]⁺.

Example 570

Compound 570 was synthesized by the same procedure as that of Example566.

¹HNMR (DMSO-d₆) δ: 2.83-2.97 (3H, m), 3.16-3.62 (2H, m), 3.56 (1H, m),3.66 (1H, d, J=11.1 Hz), 5.35 (1H, d, J=11.1 Hz), 5.73 (1H, d, J=7.4Hz), 6.68 (1H, d, J=7.4 Hz), 6.92 (1H, m), 7.06-7.21 (5H, m), 7.49 (1H,m), 7.97 (1H, d, J=8.4 Hz), 8.14 (1H, s), 8.50 (1H, d, J=3.6 Hz), 8.81(1H, d, J=2.1 Hz).

MS: m/z=449.95 [M+H]⁺.

Example 571

First Step

To a DMF (1 mL) solution of compound 563H (50.0 mg, 0.108 mmol) wasadded cesium carbonate (176 mg, 0.540 mmol), and the mixture was stirredat room temperature for 10 minutes. To the reaction solution was addedO-(2,4-dinitrophenyl)hydroxylamine (64.6 mg, 0.324 mmol), and themixture was stirred at room temperature for 9 hours. To the reactionsolution was added chloroform, and the mixture was washed with water,and dried with sodium sulfate. The solvent was distilled off, and theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with chloroform and, then, withchloroform-methanol (98:2, v/v). Concentration of an objective fractionafforded 28.3 mg of compound 571A as an amorphous substance.

MS: m/z=478 [M+H]⁺.

Second Step

Compound 571A (27.0 g, 0.057 mmol) was dissolved in a THF-methanol (1mL, 1:1, v/v) solution, 10% palladium carbon (15.0 mg) was added, andthe mixture was stirred at room temperature for 2 hours under hydrogenatmosphere. After dilution with chloroform, insolubles were removed bycelite filtration. After the filtrate was concentrated under reducedpressure, the residue was solidified with dichloromethane-ether toobtain 12.0 mg of compound 571.

MS: m/z=388 [M+H]⁺.

Example 572

Using compound 12H, and according to Example 571, compound 572 wassynthesized by the same procedure.

MS: m/z=420 [M+H]⁺.

Example 573

First Step

To a dimethylformamide (1.5 mL) solution of compound 563H (83.2 mg,0.160 mmol) was added sodium hydride (60%, 13.2 mg, 0.330 mmol) underice-cooling, the mixture was stirred for 30 minutes, thereafter,bromoacetonitrile (0.0190 mL, 0.270 mmol) was added, and the mixture wasstirred at room temperature for 1 hour. To the reaction solution wasadded an aqueous ammonium chloride solution (10%, 3 mL), and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater (10 mL) and an aqueous saturated sodium chloride solution (10 mL),and dried with sodium sulfate. The solvent was distilled off underreduced pressure, and the resulting crude product of compound 573A wasused in a next reaction without purification.

MS: m/z=502.00 [M+H]⁺.

Second Step

To an acetonitrile (4 mL) suspension of the crude product of compound573A obtained in the first step and sodium iodide (111 mg, 0.741 mmol)was added chlorotrimethylsilane (0.0920 mL, 0.720 mmol) at roomtemperature, and the mixture was stirred for 24 hours. To the reactionsolution was added an aqueous sodium hydrogen sulfite solution (10%, 10mL) and, thereafter, the mixture was extracted with chloroform. Afterthe extracts were combined, and dried with sodium sulfate, the solventwas concentrated under reduced pressure, and the resulting residue waspurified by preparative LCMS to obtain compound 573 (22.0 mg, 29.7%) asa gray white solid.

¹H-NMR (DMSO-d₆) δ: 2.86-2.95 (2H, m), 3.45-3.63 (2H, m), 4.01 (1H, m),4.30 (1H, d, J=10.8 Hz), 4.35 (1H, d, J=17.4 Hz), 4.74 (1H, d, J=17.4Hz), 5.20 (1H, m), 5.66 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=7.8 Hz), 6.73(1H, d, J=7.5 Hz), 6.83 (1H, m), 7.11-7.28 (6H, m).

MS: m/z=502.00 [M+H]⁺.

Example 574

Compound 574 was synthesized by the same procedure as that of Example573.

¹H-NMR (DMSO-d₆) δ: 4.16 (1H, dd, J=13.26, 3.53 Hz), 4.36 (1H, d,J=11.58 Hz), 4.52 (2H, dd, J=20.73, 17.54 Hz), 5.44 (1H, d, J=11.41 Hz),5.65 (1H, d, J=7.39 Hz), 6.99 (1H, d, J=7.55 Hz), 7.11-7.32 (6H, m),7.36-7.45 (2H, m), 7.58 (2H, d, J=7.39 Hz).

Example 575

Compound 575 was synthesized by the same procedure as that of Example573.

MS: m/z=425.95 [M+H]⁺.

Example 576

First Step

A dichloromethane (30 mL) solution of compound 576A (Bioorg. Med. Chem.,2003, 11, 197-206) (2.26 g, 10.2 mmol) were addedtetraisopropoxytitanium (10.0 mL, 33.1 mmol) and(S)-4-methylbenzenesulfinamide (1.29 g, 8.13 mmol) at room temperature,and the mixture was refluxed for 2 hours. The reaction solution wasice-cooled, ice water (40 ml) was added, the mixture was stirred for 1hour while temperature was retained at the same temperature, and theprecipitated solid was filtered using celite. The resulting filtrate wasextracted with dichloromethane, and magnesium sulfate was added to thecombined extracts to dry them. The solvent was distilled off, and theresulting oil was purified by silica gel column chromatography, andeluted with n-hexane-ethyl acetate (100:0→70:30, v/v). Concentration ofan objective fraction afforded 1.35 g of compound 576B as a yellowsolid.

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 2.72-2.85 (2H, m), 3.03-3.16 (2H, m),4.89 (1H, d, J=3.5 Hz), 7.09-7.25 (10H, m), 7.39-7.42 (2H, m), 8.49 (1H,d, J=3.6 Hz).

MS: m/z=360 [M+H]⁺.

Second Step

A THF (20 mL) solution of a 1M cyanodiethylaluminum toluene solution(7.51 mL, 7.51 mmol) was cooled to 0 degree, 2-propanol (0.579 mL, 7.51mmol) was added and, thereafter, the mixture was stirred for 1 hourwhile temperature was retained at the same temperature. Thereafter, thereaction solution was cooled to −60 degree, a THF (14 mL) solution ofcompound 576B was added dropwise, the mixture was stirred for 15 minuteswhile temperature was retained at the same temperature, thereafter,temperature was raised to room temperature, and the mixture was stirredovernight. The reaction solution was ice-cooled, an aqueous saturatedammonium chloride solution was added, the mixture was stirred at roomtemperature for 1 hour and 30 minutes and, thereafter, the precipitatedsolid was filtered using celite, and washed with dichloromethane. Thedichloromethane layer of the filtrate was separated, the aqueous layerwas extracted with dichloromethane, and sodium sulfate was added to thecombined extracts to dry them. The solvent was distilled off, to theresulting oil were added ethyl acetate and hexane, and the precipitatedsolid was filtered and washed to obtain 976 mg of compound 576C as awhite solid.

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 2.92-3.055 (2H, m), 3.41-3.52 (2H, m),4.25 (1H, d, J=10.8 Hz), 4.28 (1H, d, J=5.6 Hz), 4.94 (1H, dd, J=10.6,5.7 Hz), 7.14-7.41 (12H, m).

Third Step

A methanol (8 mL) suspension of compound 576C (500 mg, 1.29 mmol) wascooled to 0 degree, cobalt (II) chloride hexahydrate (123 mg, 0.517mmol) was added, and the mixture was stirred at room temperature for 30minutes. To the reaction solution was added chloroform (5 mL),thereafter, the mixture was ice-cooled, a DMF (4 mL) solution of sodiumborohydride (196 mg, 5.17 mmol) was added dropwise, and the mixture wasstirred at the same temperature for 5 minutes, and at room temperaturefor 2 hours. Then, Boc₂O (1.0 mL, 4.3 mmol) was added, and the mixturewas stirred at room temperature overnight. To the reaction solution wasadded water, the mixture was extracted with ethyl acetate, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→98:2, v/v).Concentration of an objective fraction afforded a crude product (200 mg)of compound 576D.

MS: m/z=491 [M+Na]⁺.

Fourth Step

To a methanol (6 mL) solution of the crude product (200 mg) of compound576D obtained in the third step was added TFA (0.188 mL, 2.45 mmol), andthe mixture was stirred at room temperature for 2.5 hours. To thereaction solution was added triethylamine (0.399 mL, 2.45 mmol), thesolvent was distilled off, and the resulting crude product of compound576E was used in a next reaction without purification.

MS: m/z=353 [M+H]⁺.

Fifth Step

To a toluene (4 mL) solution of the crude product of compound 576Eobtained in the fourth step was added dimethyl3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (130 mg, 0.409 mmol), andthe mixture was refluxed for 2 hours. The reaction solution wassubjected to silica gel column chromatography, and eluted withchloroform-methanol (100:0→90:10, v/v). Concentration of an objectivefraction afforded a crude product (268 mg) of compound 576F.

MS: m/z=653 [M+H]⁺.

Sixth Step

To the crude product (263 mg) of compound 576F obtained in the fifthstep was added a 4N hydrochloric acid ethyl acetate solution (3 mL), andthe mixture was stirred at room temperature for 1 hour and 30 minutes.The solvent was distilled off, to a THF (4 mL) solution of the resultingconcentrated residue was added acetone (1 mL), the mixture was stirredat room temperature for 25 minutes, thereafter, NaBH(OAc)₃ (180 mg,0.807 mmol) was added, and the mixture was stirred at room temperaturefor 1 hour and 15 minutes. Thereafter, to the reaction solution wasadded an aqueous saturated sodium bicarbonate solution (7 mL), and themixture was stirred at room temperature overnight. To the reactionsolution was added water, the mixture was extracted with chloroform, andsodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol(100:0→94:6, v/v). Concentration of an objective fraction afforded acrude product (160 mg) of compound 576G.

MS: m/z=563 [M+H]⁺.

Seventh Step

To an EtOH (4 mL) solution of the crude product (160 mg) of compound576G obtained in the sixth step was added 2N NaOH (2 mL), and themixture was stirred at room temperature for 3 hours. To the reactionsolution was added a 2N aqueous HCl solution, the mixture was extractedwith ethyl acetate, and sodium sulfate was added to the combinedextracts to dry them. The solvent was distilled off, and the resultingoil was subjected to silica gel column chromatography, and eluted withchloroform-methanol (100:0→94:6, v/v). Concentration of an objectivefraction afforded 78 mg of compound 576H as a yellow solid.

MS: m/z=549 [M+H]⁺.

Eighth Step

To compound 576H (78 mg, 0.14 mmol) was added diphenyl ether (3 mL), andthe mixture was stirred at 245 degree for 1 hour under microwaveirradiation. The reaction solution was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→90:10, v/v).Concentration of an objective fraction afforded 43 mg of compound 576Ias a bronzed oil.

MS: m/z=505 [M+H]⁺.

Ninth Step

To compound 576I (42 mg, 0.083 mmol) was added TFA (1.0 mL), and themixture was stirred at room temperature for 35 minutes. The reactionsolution was subjected to toluene azeotropy, to the resultingconcentrated residue was added an aqueous saturated sodium bicarbonatesolution, and the mixture was extracted with ethyl acetate. Sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, to the resulting oil were added ethyl acetate andisopropyl ether, and the precipitated solid was filtered and washed toobtain 14 mg of compound 576 as a pale brown solid.

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=6.7 Hz), 1.20 (3H, d, J=6.7 Hz),2.95-3.13 (2H, m), 3.28 (1H, d, J=13.1 Hz), 3.37-3.59 (2H, m), 3.75 (1H,d, J=10.3 Hz), 4.10 (1H, d, J=10.8 Hz), 4.80-4.87 (2H, m), 5.91 (1H, d,J=5.8 Hz), 6.41 (2H, t, J=6.5 Hz), 6.85 (1H, t, J=6.4 Hz), 7.05-7.35(6H, m).

MS: m/z=415 [M+H]⁺.

Example 577

First Step

To a dimethylformamide (3 mL) solution of a crude product (140 mg) ofcompound 159A was added potassium cyanide (21.0 mg, 0.323 mmol) at roomtemperature, and the mixture was stirred at 80° C. for 30 minutes, andat 100° C. for 30 minutes. The reaction solution was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/n-hexane=80%→100%) to obtaincompound 577B (41.5 mg, 33.5%) as a pale orange foam.

MS: m/z=535.25 [M+H]⁺.

Second Step

To an acetonitrile (4 mL) solution of compound 577B (41.5 mg, 0.078mmol) and sodium iodide (45.5 mg, 0.304 mmol) was addedchlorotrimethylsilane (0.0400 mL, 0.313 mmol) at room temperature, andthe mixture was stirred for 2 hours. To the reaction solution was addedwater (1 mL), the reaction solution was concentrated under reducedpressure, and the resulting residue was purified by preparative LCMS.Diethyl ether was added to the resulting residue to convert it into apowder, to obtain compound 577 (20.7 mg, 60.0%) as a gray white solid.

¹HNMR (DMSO-d₆) δ: 3.10 (3H, s), 3.51 (2H, m), 3.70 (1H, d, J=18.9 Hz),4.03 (1H, d, J=18.9 Hz), 4.46 (1H, d, J=13.4 Hz), 5.04 (1H, d, J=13.4Hz), 5.56 (1H, s), 5.69 (1H, s), 7.09-7.21 (5H, m), 7.39-7.63 (3H, m),7.64 (2H, m).

MS: m/z=445.20 [M+H]⁺.

Example 578

Compound 578 was synthesized by the same procedure as that of Example157.

¹HNMR (CDCl₃) δ: 0.97 (3H, d, J=6.6 Hz), 1.19 (3H, d, J=6.9 Hz), 3.29(3H, s), 3.97 (1H, d, J=16.1 Hz), 4.56 (1H, d, J=13.7 Hz), 4.82 (1H, m),4.96 (1H, d, J=16.1 Hz), 5.34 (1H, s), 5.97 (1H, d, J=13.7 Hz), 6.78(2H, m), 7.12 (2H, m), 7.44-7.51 (6H, m).

MS: m/z=434.10 [M+H]⁺.

Example 579

Compound 579 was synthesized by the same procedure as that of Example163.

MS: m/z=477.25 [M+H]⁺.

Example 580

First Step

To a solution of compound 155A (10.5 g, 26.9 mmol),diisopropylethylamine (11.0 mL, 63.0 mmol), 1-methylimidazole (2.60 mL,32.6 mmol) and isopropylamine (2.80 mL, 32.7 mmol) in toluene (100 mL)and acetonitrile (20 mL) was added dropwise diphenylphosphoric acidchloride (6.80 mL, 32.7 mmol) over 5 minutes under ice-cooling, and themixture was stirred under ice-cooling for 90 minutes, at roomtemperature for 90 minutes. To the reaction solution were addedtert-butyldimethylsilyl chloride (4.05 g, 26.9 mmol) and triethylamine(4.10 mL, 29.6 mmol) under ice-cooling, the mixture was stirred at roomtemperature for 80 minutes, 4-dimethylaminopyridine (164 mg, 1.35 mmol)and methylene chloride (100 mL) were added at room temperature, and themixture was stirred for 15.5 hours. To the reaction solution was addedtert-butyldimethylsilyl chloride (2.04 g, 26.9 mmol) at roomtemperature, and the mixture was stirred for 24 hours. To the reactionsolution was added a 10% aqueous acetic acid solution (100 mL) at roomtemperature, and the mixture was extracted with chloroform, the extractswere combined, washed with saturated sodium bicarbonate water (100 mL),and dried with sodium sulfate. The solvent was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/n-hexane=15%→40%) to obtaincompound 580B (6.96 g, 59.9%) as a pale yellow oil.

MS: m/z=432.25 [M+H]⁺.

Second Step

To an ethanol (50 mL) solution of compound 580B (6.96 g, 16.1 mmol) wasadded aqueous ammonia (35 mL) at room temperature, and the mixture wasstirred for 4 days. The reaction solution was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=75%→100%,methanol/chloroform=0%→15%) to obtain compound 580C (4.50 g, 64.8%) as apale orange gummy substance.

MS: m/z=431.25 [M+H]⁺.

Third Step

To a dimethylformamide (90 mL) solution of compound 580C (4.50 g, 10.5mmol) and potassium carbonate (7.27 g, 52.6 mmol) was addedO-(2,4-dinitrophenyl)hydroxylamine (6.29 g, 31.6 mmol) at roomtemperature, and the mixture was stirred for 2 days. To the reactionsolution was added chloroform (180 mL) at room temperature, theprecipitated insolubles were filtered off, the filtrated wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography(methanol/chloroform=0%→10%) to obtain compound 580D (5.28 g, quant) asa yellow solid.

MS: m/z=446.25 [M+H]⁺.

Fourth Step

To an ethanol (15 ml) solution of compound 580D (1.29 g, 2.89 mmol) wasadded paraformaldehyde (261 mg, 8.68 mmol) at room temperature, and themixture was stirred at 140° C. for 3 hours under microwave irradiation.The reaction solution was concentrated under reduce pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=50%→100%) to obtain compound 580E (2.47 g,93.0%) as a pale orange solid.

MS: m/z=458.20 [M+H]⁺.

Fifth Step

To a DMF (25 mL) solution of compound 580E (2.47 g, 5.40 mmol) wereadded cesium carbonate (5.28 g, 16.2 mmol) and bromodiphenylmethane(4.02 g, 16.3 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 2 days. To the reaction solution was added water(50 mL) under ice-cooling and, thereafter, the mixture was extractedwith ethyl acetate (150 mL×2). The extracts were combined, sequentiallywashed with water (50 mL×2) and an aqueous saturated sodium chloridesolution (50 mL), and dried with sodium sulfate. The solvent wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (ethylacetate/n-hexane=50%→100%, methanol/chloroform=10%→20%) to obtaincompound 580F (1.60 g, 47.5%) as a yellow form.

MS: m/z=624.30 [M+H]⁺.

Sixth Step

To a methanol (40 mL) solution of compound 580F (1.60 g, 2.56 mmol) wasadded hydrogen chloride (4N ethyl acetate solution, 20 mL) at roomtemperature, and the mixture was stirred for 2 hours. The reactionsolution was concentrated under reduced pressure, to the resultingresidue was added saturated sodium bicarbonate water (20 mL) at roomtemperature and, thereafter, the mixture was extracted with chloroformthree times. The extracts were combined, and dried with sodium sulfate,the solvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (ethyl acetate)to obtain compound 580G (920 mg, 70.4%) as a white foam.

MS: m/z=510.25 [M+H]⁺.

Seventh Step

To a THF (80 mL) solution of compound 580G (816 mg, 1.60 mmol) was addedmanganese dioxide (2.39 g, 27.5 mmol) at room temperature, and themixture was stirred for 19 hours. After the reaction solution wasfiltered, the filtrate was distilled off under reduced pressure, and theresulting crude product (785 mg) of compound 580H was used in a nextreaction without purification.

MS: m/z=508.20 [M+H]⁺.

Eighth Step

To a solution of the crude product (635 mg, 1.25 mmol) of compound 580Hobtained in the seventh step and amidosulfuric acid (425 mg, 4.38 mmol)in methanol (30 mL) and water (10 mL) was added dropwise a solution ofsodium chlorite (396 mg, 4.38 mmol) in water (4 mL) over 10 minutesunder ice-cooling, the mixture was stirred at room temperature for 30minutes, and a 5% aqueous sodium hydrogen sulfite solution (10 mL) wasadded. Methanol was distilled off under reduced pressure, and theresulting residue was extracted with ethyl acetate two times. Theextracts were combined, washed with an aqueous saturated sodium chloridesolution (10 mL), and dried with sodium sulfate. The filtrated wasdistilled off under reduced pressure, and the resulting crude product ofcompound 580I was used in a next reaction without purification.

MS: m/z=524.25 [M+H]⁺.

Ninth Step

To a methylene chloride (20 mL) solution of the crude product (164 mg,0.313 mmol) of compound 580I obtained in the eighth step,diisopropylethylamine (0.131 mL, and 0.751 mmol), 1-methylimidazole(0.0300 mL, 0.376 mmol) and methylamine (2.0M tetrahydrofuran solution,0.188 mL, 0.376 mmol) was added diphenylphosphoric acid chloride (0.0780mL, 0.375 mmol) at room temperature, the mixture was stirred for 3.5hours, methylamine hydrochloride (25.0 mg, 0.370 mmol) was added, andthe mixture was stirred for 6 days. The reaction solution was distilledoff under reduced pressure, and the resulting residue was purified bysilica gel column chromatography (ethyl acetate/n-hexane=75%→00%) toobtain compound 580J (45.7 mg, 27.2%) as a white foam.

MS: m/z=537.30 [M+H]⁺.

Tenth Step

To an acetonitrile (4 mL) solution of compound 580J (45.7 mg, 0.0850mmol) and sodium iodide (103 mg, 0.687 mmol) was addedchlorotrimethylsilane (0.0870 mL, 0.681 mmol) at room temperature, andthe mixture was stirred for 20 hours. To the reaction solution was addeda 5% aqueous sodium hydrogen sulfite solution (4 mL), and the mixturewas extracted with chloroform two times. After the extracts werecombined, and dried with sodium sulfate, the residue obtained byconcentration under reduced pressure was purified by preparative LCMS.Diethyl ether and n-hexane were added to the resulting residue toconvert it into a powder, to obtain compound 580 (17.1 mg, 45.0%) as awhite solid.

¹HNMR (CDCl₃) δ: 0.93 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=6.9 Hz), 2.83(3H, d, J=4.8 Hz), 4.53 (1H, d, J=13.4 Hz), 4.85 (1H, m), 4.97 (1H, d,J=13.4 Hz), 5.07 (1H, brd), 5.25 (1H, s), 5.86 (1H, s), 6.97 (2H, m),7.15-7.24 (2H, m), 7.38-7.46 (6H, m).

MS: m/z=447.20 [M+H]⁺.

Example 581

First Step

To a tert-butanol (4 mL) solution of compound 580I (398 mg, 0.760 mmol)were added triethylamine (0.158 mL, 1.14 mmol) and diphenylphosphoricacid azide (0.196 mL, 0.912 mmol) at room temperature, and the mixturewas heated to reflux for 20 hours. To the reaction solution was addedwater (20 mL) at room temperature, and the mixture was extracted withchloroform three times. The extracts were combined, and dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (methanol/chloroform=0%→10%) to obtain compound 581A (167mg, 36.9%) as a gray white solid.

MS: m/z=595.10 [M+H]⁺.

Second Step

To a methylene chloride (2 mL) solution of compound 581A (167 mg, 0.281mmol) was added trifluoroacetic acid (2 mL) at room temperature, and themixture was stirred for 1.5 hours. The reaction solution wasconcentrated under reduced pressure, and the resulting residue waspurified by preparative LCMS. Ethyl acetate, diethyl ether, and methanolwere added to the resulting residue to convert it into a powder, toobtain compound 581 (29.4 mg, 25.9%) as a white solid.

¹HNMR (DMSO-d₆) δ: 0.81 (3H, d, J=6.5 Hz), 0.98 (3H, d, J=6.5 Hz), 4.35(1H, d, J=12.6 Hz), 4.63 (1H, m), 4.68 (1H, d, J=12.6 Hz), 4.80 (1H, s),5.28 (1H, s), 6.34 (2H, s), 7.10-7.43 (8H, m), 7.81-7.83 (2H, m).

MS: m/z=404.95 [M+H]⁺.

Example 582

First Step

To an ethanol (4 mL) solution of compound 582A (200 mg, 0.470 mmol)synthesized according to the synthesis method of Example 65 was addedparaformaldehyde (14.8 mg, 0.493 mmol) at room temperature, and themixture was stirred at 140° C. for 45 minutes under microwaveirradiation. The reaction solution was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=90%→100%) to obtain compound 582B(173 mg, 84.0%) as a white solid.

MS: m/z=438.15 [M+H]⁺.

Second Step

To a methylene chloride (4 mL) solution of compound 582B (173 mg, 0.396mmol), 4-dimethylaminopyridine (5.6 mg, 0.046 mmol) and triethylamine(0.164 mL, 1.18 mmol) was added 2-fluorobenzenesulfonyl chloride (0.0790mL, 0.597 mmol) at room temperature, and the mixture was stirred for 3days. The reaction solution was distilled off under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=60%→80%) to obtain compound 582C(199 mg, 84.0%) as a white solid.

MS: m/z=596.15 [M+H]⁺.

Third Step

To an acetic acid (2 mL) solution of compound 582C (162 mg, 0.272 mmol)was added 48% aqueous hydrogen bromide (2 mL) at room temperature, andthe mixture was stirred at 100° C. for 20 minutes under microwaveirradiation. The solvent was distilled off under reduced pressure, anddiethyl ether and methanol were added to the resulting residue toconvert it into a powder, to obtain compound 582 (160 mg, quant) as ayellow solid.

¹HNMR (DMSO-d₆) δ: 4.34 (1H, d, J=14.7 Hz), 4.59 (1H, d, J=14.7 Hz),5.50 (1H, d, J=14.3 Hz), 5.81 (1H, d, J=14.3 Hz), 7.15-7.21 (2H, m),7.35-7.40 (2H, m), 7.45-7.61 (2H, m), 7.78 (1H, m), 7.93 (1H, m), 8.42(1H, s).

MS: m/z=492.10 [M+H]⁺.

Example 583, Example 584

First Step

Compound 583A (3.0 g, 0.99 mmol) synthesized according to Example 95 wasadded to toluene (300 ml) and acetic acid (30.0 ml) to dissolve, andTsOH H₂O (0.1 g, 0.526 mmol) was added at room temperature. The reactionmixture was stirred for 3 hours under heat-refluxing. Afterconcentration under reduced pressure, the residue was purified by aminosilica gel column chromatography (CHCl₃/MeOH 50:1) to obtain compound583B (1.8 g, 72.4%).

MS: m/z=312 [M+H]⁺.

Second Step

Compound 583B (233 mg, 0.748 mmol) and compound 583C (197 mg, 0.8 mmol)were suspended in THF (7.5 ml), and NaHMDS (1.123 ml, 1.123 mmol, 1M-THFsolution) was added at room temperature under nitrogen stream. Afterstirring at room temperature for 3 hours, water was added, and themixture was extracted with ethyl acetate (2×30 mL). The ethyl acetatelayer was washed with an aqueous saturated sodium chloride solution, anddried with sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (CHCl₃/MeOH 20:1) to obtain compound 583D (90 mg, 23.1%).

MS: m/z=522 [M+H]⁺.

Third Step

Compound 583D (90 mg, 0.173 mmol) was dissolved in a mixed solvent ofMeOH (3 ml) and THF (3.00 ml), and 10% palladium-carbon (90 mg, 0.846mmol) was added. The mixture was stirred for 24 hours under hydrogen (2atm) stream, and insolubles were filtered. The residue was purifiedusing HPLC (MeCN—H₂O), and diastereomers were resolved.

First Fraction (Compound 583)

(15 mg, 20.1%)

MS: m/z=432 [M+H]⁺.

Second Fraction (Compound 584)

(45 mg, 60.4%)

MS: m/z=432 [M+H]⁺.

Example 585

Compound 585 was synthesized by the same procedure as that of Example403.

¹H-NMR (DMSO-d₆) δ: 1.87-2.28 (4H, m), 3.40-3.80 (3H, m), 4.32 (1H, d,J=12.96 Hz), 5.34 (1H, t, J=7.32 Hz), 5.65 (1H, d, J=7.63 Hz), 6.90 (1H,d, J=7.78 Hz), 7.10-7.35 (5H, m).

MS: m/z=312 [M+H]⁺.

Example 586

First Step

Compound 95B (2.29 g, 8.12 mmol) was dissolved in pyridine (10 ml),iso-propyl-D₇-amine hydrochloride (1.00 g, 9.75 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.10 g, 8.12 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (3.11 g, 16.2 mmol) were added, and the mixture wasstirred at room temperature for 20 hours. The reaction solution waspoured into water, and the mixture was extracted with ethyl acetate, anddried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by silica gelcolumn chromatography, and eluted with chloroform-methanol (97:3, v/v).To the resulting compound was added diethyl ether, and the precipitatedresidue was filtered to obtain 1.36 g of a white solid 586B.

Second Step

Compound 586B (1.36 g, 4.64 mmol) obtained in the first step wasdissolved in dimethylformamide (20 ml), potassium carbonate (3.20 g,23.2 mmol) was added, and the mixture was stirred at room temperaturefor 50 minutes. 0-(2,4-dinitrophenyl)hydroxylamine (1.85 g, 9.27 mmol)was added, and the mixture was stirred at room temperature for 18 hours.To the reaction solution was added chloroform, the generated precipitatewas removed by filtration, and the filtrate was concentrated underreduced pressure. The resulting crude product was purified by aminocolumn chromatography, and eluted with chloroform-methanol (97:3, v/v)to obtain 835 mg of a colorless solid 586C.

¹H-NMR (CDCl₃) δ: 5.28 (2H, s), 5.63 (2H, s), 6.32 (1H, d, J=7.7 Hz),7.10 (1H, brs), 7.42 (6H, m).

Third Step

Compound 586C (581 mg, 1.88 mmol) obtained in the second step andparaformaldehyde-D₂ (181 mg, 5.65 mmol) were added to ethanol (12 ml),and the mixture was stirred at 140° C. for 30 minutes under microwaveirradiation. The reaction solution was concentrated under reducedpressure, and the resulting crude product was purified by amino columnchromatography, and eluted with chloroform-methanol (97:3, v/v). To theresulting compound was added diethyl ether, and the precipitated residuewas filtered to obtain 140 mg of white solid 586D.

¹H-NMR (CDCl₃) δ: 4.39 (2H, d, J=8.1 Hz), 5.36 (2H, s), 5.42 (1H, t,J=8.0 Hz), 6.37 (1H, d, J=7.6 Hz), 7.48 (6H, m).

Fourth Step

Compound 586E (972 mg, 5.78 mmol) was dissolved in tetrahydrofuran (10ml), sodium hydride (60%, 231 mg, 5.78 mmol) and benzyl bromide-D₂ (1.00g, 5.78 mmol) were added at 0° C., and the mixture was stirred at 60° C.for 30 minutes. The reaction solution was added to dilute hydrochloricacid, the mixture was extracted with ethyl acetate, and the organiclayer was washed with an aqueous sodium bicarbonate solution. Thesolvent was distilled off under reduced pressure to obtain 1.48 g of awhite solid 586F.

¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 7.17-7.48 (8H, m), 8.00 (1H, dd, J=7.8,1.3 Hz).

Fifth Step

Compound 586F (1.50 g, 5.76 mmol) obtained in the fourth step wasdissolved in methanol (20 ml) and tetrahydrofuran (20 ml), a 2N aqueoussodium hydroxide solution (14.4 ml, 28.8 mmol) was added, and themixture was stirred at room temperature for 3 hours. To the reactionsolution was added dilute hydrochloric acid to make the solution acidic,the mixture was extracted with ethyl acetate, and the organic layer waswashed with an aqueous saturated sodium chloride solution, and driedwith sodium sulfate. The solvent was distilled off under reducedpressure, to the resulting compound were added n-hexane-ethyl acetate,and the precipitated residue was filtered to obtain 1.17 g of a whitesolid 586G.

¹H-NMR (CDCl₃) δ: 7.18-7.48 (8H, m), 8.11 (1H, dd, J=7.9, 1.6 Hz).

Sixth Step

To compound 586G (1.15 g, 4.67 mmol) obtained in the fifth step wasadded toluene (10 ml), dimethylformamide (0.100 ml, 1.29 mmol) andthionyl chloride (0.410 ml, 5.60 mmol) were added, and the mixture wasstirred at 130° C. for 1.5 hours. After cooled to room temperature, thereaction solution was concentrated under reduced pressure. To theresulting compound was added n-hexane, and the precipitated residue wasfiltered to obtain 1.16 g of a white solid. To aluminum chloride (718mg, 5.38 mmol) were added dichloromethane (10 ml) and nitromethane (0.5ml), a dichloromethane solution (5 ml) of 500 mg of the compoundobtained above was added at 0° C., and the mixture was stirred at roomtemperature for 5 hours. To the reaction solution was added an aqueoussodium hydroxide solution, and the mixture was extracted with methylenechloride, and the organic layer was dried with sodium sulfate. Thesolvent was concentrated under reduced pressure, and the resulting crudeproduct was purified by silica gel column chromatography, and elutedwith n-hexane-ethyl acetate (4:1, v/v). To the resulting compound wasadded n-hexane, and the precipitated residue was filtered to obtain 155mg of a pale yellow solid 586H.

¹H-NMR (CDCl₃) δ: 7.21-7.39 (6H, m), 7.46 (1H, td, J=7.5, 1.4 Hz), 7.59(1H, dd, J=7.5, 1.4 Hz), 8.21 (1H, dd, J=8.0, 1.0 Hz).

Seventh Step

Compound 586H (150 mg, 0.657 mmol) obtained in the sixth step wasdissolved in tetrahydrofuran (3 ml), lithium aluminum hydride-D₄ (13.8mg, 0.329 mmol) was added at 0° C., and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added dilutehydrochloric acid, the mixture was extracted with ethyl acetate, anddried with sodium sulfate, and the solvent was distilled off underreduced pressure. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 114 mg of a white solid 586I.

¹H-NMR (CDCl₃) δ: 7.17 (6H, m), 7.40-7.52 (2H, m).

Eighth Step

Compound 586D (76.0 mg, 0.236 mmol) and 5861 (54.5 mg, 0.235 mmmol) weredissolved in acetic acid (3.2 ml), and concentrated sulfuric acid (0.8ml) was added dropwise under water-cooling. After the mixture wasstirred at room temperature for 30 minutes, the mixture was poured intowater, and extracted with ethyl acetate. The organic layer was driedwith sodium sulfate, the solvent was distilled off under reducedpressure, to the resulting crude product were added ethylacetate-diethyl ether, and the precipitated residue was filtered toobtain 32 mg of a white solid 586.

¹H-NMR (DMSO-d₆) δ: 5.57 (1H, d, J=7.3 Hz), 6.82-7.44 (9H, m).

MS: m/z=446 [M+H]⁺.

Using a commercially available heavy hydrogen reagent, and according toExample 586, compounds 587 to 591 were synthesized.

Example 587

Example 588

MS: m/z=436 [M+H]⁺

¹H-NMR (DMSO-d₆) δ: 3.87 (1H, d, J=13.4 Hz), 5.58 (1H, d, J=7.8 Hz),5.60 (1H, d, J=12.6 Hz), 6.81-7.48 (9H, m).

Example 589

MS: m/z=441 [M+H]⁺

Example 590

MS: m/z=435 [M+H]⁺

Example 591

MS: m/z=436 [M+H]⁺

The following EX-1 to EX-29 can be also synthesized like the Examples,and are a preferable embodiment of the present invention.

Further, the following combinations of substituents can be alsosynthesized like the above Examples, and are a preferable embodiment ofthe present invention.

Compounds in which, in the following formula (I) or (II):

combinations of R³ or R^(3a), as well as R⁷ or R^(7a) of the followingformula (I′) or (II′):

[Chemical Formula 672]

are selected from the following Tables 6 to 10 and Table 11,respectively.Combinations of (R³, R⁷) or (R^(3a), R^(7a))=(R3-1, R7-1), (R3-1, R7-2),(R3-1, R7-3), (R3-1, R7-4), (R3-1, R7-5), (R3-1, R7-6), (R3-1, R7-7),(R3-1, R7-8), (R3-1, R7-9), (R3-1, R7-10), (R3-1, R7-11), (R3-1, R7-12),(R3-1, R7-13), (R3-1, R7-14), (R3-1, R7-15), (R3-1, R7-16), (R3-1,R7-17), (R3-1, R7-18), (R3-1, R7-19), (R3-1, R7-20), (R3-1, R7-21),(R3-1, R7-22), (R3-1, R7-23), (R3-1, R7-24), (R3-1, R7-25), (R3-1,R7-26), (R3-1, R7-27), (R3-1, R7-28), (R3-1, R7-29), (R3-1, R7-30),(R3-1, R7-31), (R3-1, R7-32), (R3-1, R7-33), (R3-1, R7-34), (R3-1,R7-35), (R3-1, R7-36), (R3-1, R7-37), (R3-1, R7-38), (R3-1, R7-39),(R3-1, R7-40), (R3-1, R7-41), (R3-1, R7-42), (R3-1, R7-43), (R3-1,R7-44), (R3-1, R7-45), (R3-1, R7-46), (R3-1, R7-47), (R3-1, R7-48),(R3-1, R7-49), (R3-1, R7-50), (R3-1, R7-51), (R3-1, R7-52), (R3-1,R7-53), (R3-1, R7-54), (R3-1, R7-55), (R3-1, R7-56), (R3-1, R7-57),(R3-1, R7-58), (R3-1, R7-59), (R3-1, R7-60), (R3-1, R7-61), (R3-1,R7-62), (R3-1, R7-63), (R3-1, R7-64), (R3-1, R7-65), (R3-1, R7-66),(R3-1, R7-67), (R3-1, R7-68), (R3-1, R7-69), (R3-1, R7-70), (R3-1,R7-71), (R3-1, R7-72), (R3-1, R7-73), (R3-1, R7-74), (R3-1, R7-75),(R3-1, R7-76), (R3-1, R7-77),(R3-2, R7-1), (R3-2, R7-2), (R3-2, R7-3), (R3-2, R7-4), (R3-2, R7-5),(R3-2, R7-6), (R3-2, R7-7), (R3-2, R7-8), (R3-2, R7-9), (R3-2, R7-10),(R3-2, R7-11), (R3-2, R7-12), (R3-2, R7-13), (R3-2, R7-14), (R3-2,R7-15), (R3-2, R7-16), (R3-2, R7-17), (R3-2, R7-18), (R3-2, R7-19),(R3-2, R7-20), (R3-2, R7-21), (R3-2, R7-22), (R3-2, R7-23), (R3-2,R7-24), (R3-2, R7-25), (R3-2, R7-26), (R3-2, R7-27), (R3-2, R7-28),(R3-2, R7-29), (R3-2, R7-30), (R3-2, R7-31), (R3-2, R7-32), (R3-2,R7-33), (R3-2, R7-34), (R3-2, R7-35), (R3-2, R7-36), (R3-2, R7-37),(R3-2, R7-38), (R3-2, R7-39), (R3-2, R7-40), (R3-2, R7-41), (R3-2,R7-42), (R3-2, R7-43), (R3-2, R7-44), (R3-2, R7-45), (R3-2, R7-46),(R3-2, R7-47), (R3-2, R7-48), (R3-2, R7-49), (R3-2, R7-50), (R3-2,R7-51), (R3-2, R7-52), (R3-2, R7-53), (R3-2, R7-54), (R3-2, R7-55),(R3-2, R7-56), (R3-2, R7-57), (R3-2, R7-58), (R3-2, R7-59), (R3-2,R7-60), (R3-2, R7-61), (R3-2, R7-62), (R3-2, R7-63), (R3-2, R7-64),(R3-2, R7-65), (R3-2, R7-66), (R3-2, R7-67), (R3-2, R7-68), (R3-2,R7-69), (R3-2, R7-70), (R3-2, R7-71), (R3-2, R7-72), (R3-2, R7-73),(R3-2, R7-74), (R3-2, R7-75), (R3-2, R7-76), (R3-2, R7-77),(R3-3, R7-1), (R3-3, R7-2), (R3-3, R7-3), (R3-3, R7-4), (R3-3, R7-5),(R3-3, R7-6), (R3-3, R7-7), (R3-3, R7-8), (R3-3, R7-9), (R3-3, R7-10),(R3-3, R7-11), (R3-3, R7-12), (R3-3, R7-13), (R3-3, R7-14), (R3-3,R7-15), (R3-3, R7-16), (R3-3, R7-17), (R3-3, R7-18), (R3-3, R7-19),(R3-3, R7-20), (R3-3, R7-21), (R3-3, R7-22), (R3-3, R7-23), (R3-3,R7-24), (R3-3, R7-25), (R3-3, R7-26), (R3-3, R7-27), (R3-3, R7-28),(R3-3, R7-29), (R3-3, R7-30), (R3-3, R7-31), (R3-3, R7-32), (R3-3,R7-33), (R3-3, R7-34), (R3-3, R7-35), (R3-3, R7-36), (R3-3, R7-37),(R3-3, R7-38), (R3-3, R7-39), (R3-3, R7-40), (R3-3, R7-41), (R3-3,R7-42), (R3-3, R7-43), (R3-3, R7-44), (R3-3, R7-45), (R3-3, R7-46),(R3-3, R7-47), (R3-3, R7-48), (R3-3, R7-49), (R3-3, R7-50), (R3-3,R7-51), (R3-3, R7-52), (R3-3, R7-53), (R3-3, R7-54), (R3-3, R7-55),(R3-3, R7-56), (R3-3, R7-57), (R3-3, R7-58), (R3-3, R7-59), (R3-3,R7-60), (R3-3, R7-61), (R3-3, R7-62), (R3-3, R7-63), (R3-3, R7-64),(R3-3, R7-65), (R3-3, R7-66), (R3-3, R7-67), (R3-3, R7-68), (R3-3,R7-69), (R3-3, R7-70), (R3-3, R7-71), (R3-3, R7-72), (R3-3, R7-73),(R3-3, R7-74), (R3-3, R7-75), (R3-3, R7-76), (R3-3, R7-77).

TABLE 6 R³ or R^(3a) R3-1

R3-2

R3-3

TABLE 7 R⁷ or R^(7a) R7-1 

R7-2 

R7-3 

R7-4 

R7-5 

R7-6 

R7-7 

R7-8 

R7-9 

R7-10

R7-11

R7-12

R7-13

R7-14

R7-15

R7-16

R7-17

R7-18

TABLE 8 R⁷ or R^(7a) R7-19

R7-20

R7-21

R7-22

R7-23

R7-24

R7-25

R7-26

R7-27

R7-28

R7-29

R7-30

R7-31

R7-32

R7-33

R7-34

R7-35

R7-36

TABLE 9 R⁷ or R^(7a) R7-37

R7-38

R7-39

R7-40

R7-41

R7-42

R7-43

R7-44

R7-45

R7-46

R7-47

R7-48

R7-49

R7-50

R7-51

R7-52

R7-53

R7-54

TABLE 10 R⁷ or R^(7a) R7-55

R7-56

R7-57

R7-58

R7-59

R7-60

R7-61

R7-62

R7-63

R7-64

R7-65

R7-66

R7-67

R7-68

R7-69

R7-70

R7-71

R7-72

TABLE 11 R⁷ or R^(7a) R7-73

R7-74

R7-75

R7-76

R7-77

As Reference Examples, a method for synthesizing intermediates usefulfor carrying out the present application is shown below.

Reference Example 1

First Step

A solution of benzyl alcohol (1.00 g, 9.25 mmol) in THF (3 ml) was addedto a suspension of sodium tert-pentoxide (2.55 g, 23.2 mmol) in THF (4ml) at room temperature under nitrogen atmosphere, and the mixture wasstirred at 40° C. for 2 hours. This reaction solution was cooled in anice bath, and a solution of compound 1a (1.53 g, 10.2 mmol) in THF (3ml) was added dropwise at 0 to 10° C. After the reaction solution wasstirred at room temperature for 2 hours, 2 N hydrochloric acid (15 ml)was added, followed by extraction with ethyl acetate two times. Thecombined extracts were washed sequentially with water, saturated sodiumbicarbonate water, water and saturated sodium chloride water, and thendried with anhydrous sodium sulfate. The solvent was distilled off, andthe resulting oil was purified by silica gel column chromatography(n-hexane-ethyl acetate 4:1, v/v) to obtain 1.89 g (yield 92%) ofcompound 1b as an oil product.

¹H-NMR (CDCl₃) δ: 3.56 (2H, s), 3.71 (3H, s), 4.14 (2H, s), 4.59 (2H,s), 7.27-7.42 (5H, m).

Second Step

Compound 1b (1.80 g, 8.1 mmol) was dissolved in 1,4-dioxane (18 mL),N,N-dimethylformamide dimethyl acetal (1.45 g, 12.2 mmol) was added, andthe mixture was stirred at room temperature for 6 hours. The reactionsolution was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate1:4, v/v) to obtain 1.77 g (yield 79%) of compound 1c as an oil product.

¹H-NMR (CDCl₃) δ: 2.90 (3H, br), 3.25 (3H, br), 3.69 (3H, s), 4.45 (2H,s), 4.59 (2H, s), 7.24-7.40 (5H, m), 7.73 (s, 1H).

Third Step

Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41mmol) and DMI (3 ml) were added to a three-neck flask under nitrogenatmosphere, and a solution of compound 1c (0.50 g, 1.80 mmol) in DMI (2ml) was added dropwise thereto at 25 to 30° C. After stirring at roomtemperature for 7 hours, 2N hydrochloric acid (10 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was extracted with ethyl acetate two times, and the combinedextracts were washed sequentially with water, saturated sodiumbicarbonate water, water and saturated sodium chloride water, and thendried with anhydrous sodium sulfate. The solvent was distilled off, andthe resulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 2:1 to 1:1, v/v) to obtain 488 mg (yield 85%) ofcompound id as a white crystal.

¹H-NMR (CDCl₃) δ: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40(3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).

Reference Example 2

First Step

A solution of benzyl alcohol (0.66 g, 6.1 mmol) in DMI (3 ml) was addedto a suspension of sodium tert-pentoxide (1.67 g, 15.2 mmol) in DMI (4ml) at room temperature under nitrogen atmosphere, and the mixture wasstirred at 40° C. for 2 hours. This reaction solution was cooled in anice bath, and a solution of compound 2a (1.10 g, 6.68 mmol) in DMI (3ml) was added dropwise at 0 to 10° C. The reaction solution was stirredat 0 to 5° C. for 2 hours, and at room temperature for 3 hours, and 2Nhydrochloric acid (15 ml) was added, followed by extraction with ethylacetate two times. The combined extracts were washed sequentially withwater, saturated sodium bicarbonate water, water and saturated sodiumchloride water, and then dried with anhydrous sodium sulfate. Thesolvent was distilled off, and the resulting oil product was purified bysilica gel column chromatography (n-hexane-ethyl acetate 4:1, v/v) toobtain 1.29 g (yield 90%) of compound 2b as an oil product.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 3.54 (2H, s), 4.14 (2H, s),4.17 (2H, q, J=7.2 Hz), 4.59 (2H, s), 7.28-7.40 (5H, m).

Second Step

Compound 2b (9.73 g, 41.2 mmol) was dissolved in toluene (45 ml),N,N-dimethylformamide dimethyl acetal (7.36 g, 61.8 mmol) was added, andthe mixture was stirred at room temperature for 5 hours. Water was addedto the reaction solution, followed by extraction with ethyl acetate twotimes. The combined extracts were washed sequentially with water, andsaturated sodium chloride water, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off, and the resulting oil productwas purified by silica gel column chromatography (n-hexane-ethyl acetate1:1 to 3:7, v/v) to obtain 7.90 g (yield 66%) of compound 2c as an oilproduct.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.95 (3H, br), 3.22 (3H, br),4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.59 (2H, s), 7.22-7.40 (5H, m),7.73 (1H, s).

Third Step

Sodium tert-butoxide (495 mg, 5.15 mmol) and DMI (2 ml) were added to athree-neck flask under nitrogen atmosphere, and dimethyl oxalate (608mg, 5.15 mmol) and a solution of compound 2c (0.50 g, 1.72 mmol) in DMI(3 ml) was added dropwise at 25 to 30° C. After stirring at roomtemperature for 4 hours, 2N hydrochloric acid (10 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was extracted with toluene two times, and the combined extractswere washed sequentially with water, saturated sodium bicarbonate water,water and saturated sodium chloride water, and then dried with anhydroussodium sulfate. The solvent was distilled off, and the resulting residuewas purified by silica gel column chromatography (n-hexane-ethyl acetate2:1, v/v) to obtain 420 mg (yield 74%) of compound 2d as a whitecrystal.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 3.88 (3H, s), 4.39 (2H, q,J=7.2 Hz), 5.34 (2H, s), 7.30-7.41 (3H, m), 7.45-7.50 (2H, m), 8.48 (1H,s).

Reference Example 3

First Step

N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was addeddropwise to compound 3a (5.0 g, 30.4 mmol) at 0° C. under cooling. Afterstirring at 0° C. for 1 hour, 100 ml of ethyl acetate was added to thereaction solution, followed by washing with 0.5N hydrochloric acid (50ml). The aqueous layer was separated, and extracted with ethyl acetate(50 ml). The organic layers were combined, washed sequentially withsaturated sodium bicarbonate water and saturated sodium chloride water,and then dried with anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 1:1 (v/v)→ethyl acetate) toobtain 4.49 g (yield 67%) of compound 3b as an oil product.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.90 (3H, br s), 3.29 (3H, brs), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).

Second Step

Lithium hexamethyldisilazide (1.0 M toluene solution, 49 ml, 49.0 mmol)was diluted with tetrahydrofuran (44 ml), a solution of compound 3b(4.49 g, 20.4 mmol) in tetrahydrofuran (10 ml) was added dropwisethereto at −78° C. under cooling, and a solution of ethyl oxalylchloride (3.35 g, 24.5 mmol) in tetrahydrofuran (10 ml) was addeddropwise. After stirring at −78° C. for 2 hours, temperature was raisedto 0° C. After 2N hydrochloric acid was added to the reaction solution,and the mixture was stirred for 20 minutes, the solution was extractedwith ethyl acetate (200 ml×2), and the organic layer was washed withsaturated sodium bicarbonate water and saturated sodium chloride waterand then dried with anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 7:3→5:5→0:10 (v/v)) to obtain1.77 g (yield 31%) of compound 3c as a white solid.

¹H-NMR (CDCl₃) δ: 1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).

Third Step

Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to asolution of compound 3c (300 mg, 1.09 mmol) in ethanol (6 ml) at 0° C.,and the mixture was stirred at 0° C. for 1 hour and 30 minutes, at roomtemperature for 18 hours and, then, at 60° C. for 4 hours. After thesolvent was distilled off from the reaction solvent under reducedpressure, the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 252 mg(yield 64%) of compound 3d as an oil product.

¹H-NMR (CDCl₃) δ: 1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J=5.2Hz), 4.37 (3H, q, J=7.2 Hz), 4.50 (2H, q, J=7.2 Hz), 8.16 (1H, s).

Reference Example 4

First Step

N,N-dimethylformamide dimethyl acetal (12.2 ml, 92.2 mmol) was addeddropwise to compound 4a (10.0 g, 76.8 mmol) at 0° C. under cooling.After stirring at 0° C. for 1 hour and 30 minutes and, then, at roomtemperature for 2 hours and 30 minutes, 100 ml of ethyl acetate wasadded to the reaction solution, and the solvent was distilled off. Theresulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 12.45 g (yield 88%) ofcompound 4b as an oil product.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.33 (3H, s), 3.04 (6H, br s),4.23 (2H, q, J=7.2 Hz), 7.68 (1H, s).

Second Step

Lithium hexamethyldisilazide (1.0M toluene solution, 24 ml, 24.0 mmol)was diluted with tetrahydrofuran (20 ml), a solution of compound 4b(1.85 g, 10.0 mmol) in tetrahydrofuran (5 ml) was added dropwise theretoat −78° C. under cooling, and a solution of ethyl oxalyl chloride (1.34ml, 12.0 mmol) in tetrahydrofuran (5 ml) was added dropwise. Afterstirring at −78° C. for 2 hours, 2N-hydrochloric acid was added to thereaction solution, and the mixture was stirred at room temperature for20 minutes. The solution was extracted with ethyl acetate, and theorganic layer was washed sequentially with saturated sodium bicarbonatewater and saturated sodium chloride water, and then dried with anhydroussodium sulfate. The solvent was distilled off, and the resulting residuewas purified by silica gel column chromatography (n-hexane-ethyl acetate75:25→455:5 (v/v)) to obtain 1.03 g (yield 43%) of compound 4c as abrown oil product.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.4 Hz),4.33-4.47 (4H, m), 7.19 (1H, s), 8.54 (1H, s).

Third Step

Aminoacetaldehyde dimethyl acetal (0.34 ml, 3.11 mmol) was added to asolution of compound 4c (680 mg, 2.83 mmol) in ethanol (6.8 ml) at 0°C., and it was allowed to stand at room temperature for 16 hours. Afterthe solvent was distilled off from the reaction solution under reducedpressure, the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 90:10 (v/v)) to obtain 875 mg(yield 94%) of compound 4d as an oil product.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.1 Hz), 3.40(6H, s), 4.33 (2H, d, J=4.7 Hz), 4.37 (4H, q, J=7.1 Hz), 4.49 (1H, t,J=4.7 Hz), 7.06 (1H, s), 8.17 (1H, s).

Fourth Step

N-bromosuccinimide (1.46 g, 8.18 mmol) was added to a solution ofcompound 4d (2.68 g, 8.18 mmol) in N,N-dimethylformamide (10 ml), andthe mixture was stirred at room temperature for 48 hours. Aftersaturated sodium bicarbonate water was added to the reaction solution,the solution was extracted with ethyl acetate, and the organic layer waswashed sequentially with water and saturated sodium chloride water, andthen dried with anhydrous sodium sulfate. The solvent was distilled off,and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 90:10 (v/v)) to obtain 2.83 g(yield 85%) of compound 4e as an oil product.

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 1.48 (3H, t, J=7.1 Hz), 3.42(6H, s), 3.90 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 4.53 (3H, q,J=14.3 Hz), 4.54 (3H, s), 4.57 (3H, t, J=5.4 Hz), 8.19 (1H, s).

Reference Example 5

First Step

Compound 5a (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethylacetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and themixture was stirred at room temperature for 11 hours. The solvent wasdistilled off from the reaction solution under reduced pressure, and theresulting residue (containing compound 5b) was used in Second stepwithout purification.

Second Step

Sodium tert-butoxide (400 mg, 4.16 mmol) was suspended in dimethylimidazolidinone (5 ml), a solution of the crude product obtained inFirst step in dimethylimidazolidinone (5 ml) was added thereto, asolution of dimethyl oxalate (983 mg, 8.32 mmol) in THF (10 ml) wasadded dropwise, and the mixture was stirred at room temperature for 45minutes. The reaction solution was poured into 2N hydrochloricacid-methanol (20 ml), and the mixture was stirred at 0° C. for 20minutes. Water was added, the solution was extracted with ethyl acetate,and the organic layer was washed sequentially with water, saturatedsodium bicarbonate water, and saturated sodium chloride water, and driedwith anhydrous sodium sulfate. After the solvent was distilled off, theresulting residue was purified by silica gel column chromatography toobtain 222 mg (yield: 22% from 5a) of compound 5c.

Reference Example 6

First Step

Lithium hexamethyldisilazide (1.0M toluene solution, 12 ml, 12.0 mmol)was diluted with tetrahydrofuran (11 ml), a solution of compound 6a(1.46 g, 5.0 mmol) in tetrahydrofuran (2 ml) was added dropwise theretoat −78° C. under cooling, and a solution of ethyl oxalyl chloride (0.67ml, 6.0 mmol) in tetrahydrofuran (2 ml) was added dropwise. Afterstirring at −78° C. for 2 hours, ammonium acetate (500 mg) and aceticacid (10 ml) were added to the reaction solution, and the mixture wasstirred at 65° C. for 1 hour and 30 minutes. Water was added to thereaction solution, the solvent was extracted with ethyl acetate, and theorganic layer was washed sequentially with water, and saturated sodiumbicarbonate water, and dried with anhydrous sodium sulfate. The solventwas distilled off, and the resulting residue was purified by silica gelcolumn chromatography (N-hexane-ethyl acetate 55:45→45:55 (v/v)) toobtain 505.1 mg of compound 6B as a yellow solid. It was washed withisopropyl ether-hexane (1:2), and dried under reduced pressure to obtain416.8 mg (yield 24%) of Compound 6b as a yellow crystal.

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 1.46 (3H, t, J=7.1 Hz), 4.40(2H, q, J=7.2 Hz), 4.50 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.33-7.41 (3H,m), 7.49-7.52 (2H, m), 8.76 (1H, s), 11.61 (1H, br s).

Second Step

Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde dimethylacetal (38.0 mg, 0.23 mmol) were added to a solution of compound 6b(51.8 mg, 0.15 mmol) in N,N-dimethylformamide (1 ml), and the mixturewas stirred at room temperature overnight. Cesium carbonate (73.3 mg,0.23 mmol) and bromoacetaldehyde dimethyl acetal (38.0 mg, 0.23 mmol)were further added, and the mixture was further stirred at 100° C. for20 minutes. After water was added to the reaction solution, the solutionwas extracted with ethyl acetate, and the organic layer was washedsequentially with water and saturated sodium chloride water, and driedwith anhydrous sodium sulfate. The solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 50:50→30:70 (v/v)) to obtain 35.3 mg (yield 54%)of compound 6c as a colorless oil product.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz), 3.39(6H, s), 3.91 (2H, d, J=5.0 Hz), 4.29 (2H, q, J=7.1 Hz), 4.40 (2H, q,J=7.2 Hz), 4.50 (1H, t, J=5.0 Hz), 5.30 (2H, s), 7.31-7.37 (3H, m),7.43-7.46 (2H, m), 8.12 (1H, s).

Reference Example 7

First Step

Aminoacetaldehyde dimethyl acetal (7.80 mmol) was added to a solution ofcompound 7a (900 mg, 2.60 mmol) in ethanol (5 ml), and the mixture wasstirred at room temperature for 22 hours. Ethyl acetate (5 ml) and water(5 ml) were added to the reaction solution, followed by extraction withethyl acetate (5 ml). After the organic layer was washed with water (10ml), the solvent was distilled off, and the resulting residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate2:1) to obtain 0.37 g (yield 33%) of compound 7b as a colorless oilproduct.

¹H-NMR (CDCl₃) δ: 7.90 (1H, s), 7.45-7.43 (5H, m), 5.30 (2H, s), 4.51(1H, t, J=5.1 Hz), 4.40 (2H, q, J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 3.91(2H, d, J=5.1 Hz), 3.46 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.26 (3H, t,J=7.1 Hz).

The compounds in connection with the present invention are useful forsymptoms and/or diseases which are induced by influenza virus. Forexample, they are useful for treating and/or preventing, or improvingsymptoms of, cold-like symptoms accompanying fever, algor, headache,muscular pain, general malaise etc., airway inflammation symptoms suchas pharyngalgia, nasal secretion, nasal congestion, cough, sputum etc.,gastrointestinal symptoms such as abdominal pain, vomitus, diarrhea etc.and, further, complications accompanying secondary infection such asacute encephalopathy and pneumonia.

Since the compounds in connection with the present invention have theeffects such as inhibitory activity on high cap structure-dependentendonuclease, and high selectivity due to a virus-specific enzyme, theycan be medicaments having reduced side effects. Further, since thecompounds in connection with the present invention have advantages thatmetabolism stability is high, solubility is high, oral absorbability ishigh, good bioavailability is exhibited, good clearance is exhibited,pulmonary transitivity is high, a half life is long, a non-proteinbinding rate is high, hERG channel inhibition is low, CYP inhibition islow, CPE (CytoPathic Effect) inhibiting effect is recognized, and/ornegativity is exhibited in a phototoxicity test, an Ames test and a genetoxicity test, they can be excellent medicaments.

The compounds in connection with the present invention can beadministered orally or parenterally. In the case of oral administration,the present compounds can be also used as a normal preparation, forexample, as any dosage form of solid preparations such as tablets,powders, granules, capsules etc.; solutions; oleaginous suspensions; orliquid preparations such as syrups or elixirs etc. In the case ofparenteral administration, the compounds in connection with the presentinvention can be used as aqueous or oleaginous suspension injectables,or nose drops. Upon preparation of them, conventional excipients,binders, lubricants, aqueous solvents, oleaginous solvents, emulsifiers,suspending agents, preservatives, stabilizers etc. can be arbitrarilyused. The pharmaceutical composition of the present invention can beproduced by combining (for example, mixing) a therapeutically effectiveamount of the present compound with pharmaceutically acceptable carriersor diluents.

A dose of the compounds in connection with the present invention isdifferent depending on an administration method, an age, a weight andthe state of a patient, and a kind of a disease and, usually, in thecase of oral administration, about 0.05 mg to 3000 mg, preferably about0.1 mg to 1000 mg per adult a day may be administered, if necessary, bydivision. In addition, in the case of parenteral administration, about0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg per adult a dayis administered.

Test Example 1 Measurement of Cap-Dependant Endonuclease (CEN)Inhibitory Activity 1) Preparation of Substrate

30mer RNA(5′-pp-[m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCUCUA-BHQ2-3′:manufactured by Japan Bioservice) in which G at a 5′ end isdiphosphate-modified, a hydroxy group at 2′ position ismethoxylation-modified, U sixth from a 5′ end is labelled with Cy3, anda 3′ end is labelled with BHQ2 was purchased, and a cap structure wasadded using ScriptCap system manufactured by EPICENTRE (a product wasm7G [5′]-ppp-[5′] [m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCUCUA(-BHQ2)-3′). This was separated and purified by denaturedpolyacrylamide gel electrophoresis, and used as a substrate.

2) Preparation of Enzyme

RNP was prepared from a virus particle using standard method (ReferenceDocument: VIROLOGY (1976) 73, p 327-338 OLGA M. ROCHOVANSKY).Specifically, A/WSN/33 virus (1×10³ PFU/mL, 200 μL) was innoculated in a10 days old embryonated chicken egg. After incubation at 37° C. for 2days, the allantoic fluid of the chicken egg was recovered. A virusparticle was purified by ultracentrifugation using 20% sucrose,solubilized using Triton X-100 and lysolecithin, and an RNP fraction(50-70% glycerol fraction) was collected by ultracentrifugation using a30-70% glycerol density gradient, and was used as an enzyme solution(containing approximately 1 nM PB1•PB2•PA complex).

3) Enzymatic Reaction

An enzymatic reaction solution (2.5 μL) (composition: 53 mMTris-hydrochloride (pH 7.8), 1 mM MgCl₂, 1.25 mM dithiothreitol, 80 mMNaCl, 12.5% glycerol, enzyme solution 0.15 μL) was dispensed into a384-well plate made of polypropylene. Then, 0.5 μL of a test substancesolution which had been serially diluted with dimethyl sulfoxide (DMSO)was added to the plate. As a positive control (PC) or a negative control(NC), 0.5 μL of DMSO was added to the plate respectively. Each plate wasmixed well. Then, 2 μL of a substrate solution (1.4 nM substrate RNA,0.05% Tween20) was added to initiate a reaction. After room temperatureincubation for 60 minutes, 1 μL of the reaction solution was collectedand added to 10 μL of a Hi-Di formamide solution (containing GeneScan120 Liz Size Standard as a sizing marker: manufactured by AppliedBiosystem (ABI)) in order to stop the reaction. For NC, the reaction wasstopped in advance by adding EDTA (4.5 mM) before initiation of thereaction (all concentrations described above are final concentrations).

3) Measurement of Inhibition Ratio (IC₅₀ Value)

The solution for which the reaction was stopped was heated at 85° C. for5 minutes, rapidly cooled on ice for 2 minutes, and analyzed with an ABIPRIZM 3730 genetic analyzer. A peak of the cap-dependent endonucleaseproduct was quantitated by analysis software ABI Genemapper, a CENreaction inhibition ratio (%) of a test compound was obtained by settingfluorescent intensities of PC and NC to be 0% inhibition and 100%inhibition, respectively, an IC₅₀ value was obtained using curve fittingsoftware (XLfit2.0:Model 205 (manufactured IDBS etc.)). The IC₅₀ valuesof test substances are shown in Table 12-21.

Test Example 2 CYP Inhibition Test

Using commercially available pooled human hepatic microsome, andemploying, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2),tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation(CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedinehydroxylation as typical substrate metabolism reactions of human mainfive CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitorydegree of each metabolite production amount by a test compound wasassessed

The reaction conditions were as follows: substrate, 0.5 mol/Lethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/LS-mephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/Lterfenedine (CYP3A⁴); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; testdrug concentration, 1, 5, 10, 20 μmol/L (four points).

Each five kinds of substrates, human hepatic microsome, or a test drugin 50 mM Hepes buffer as a reaction solution was added to a 96-wellplate at the composition as described above, NADPH, as a cofactor wasadded to initiate metabolism reactions as markers and, after theincubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v)solution was added to stop the reaction. After the centrifugation at3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in thesupernatant was quantified by a fluorescent multilabel counter andtributamide hydroxide (CYP2CP metabolite), mephenytoin 4′ hydroxide(CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), andterfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solutionand IC₅₀ was calculated by reverse presumption by a logistic model usinga concentration and an inhibition rate.

Test Example 3 Solubility Test

The solubility of each compound is determined under 1% DMSO additionconditions. A 10 mM solution of the compound is prepared with DMSO, and6 μL of the compound solution is added to 594 μL of an artificialintestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are addedto 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach1000 mL) with pH of 6.8. The mixture is left standing for 16 hours at25° C., and the mixture is vacuum-filtered. The filtrate is two-folddiluted with methanol/water=1/1, and the compound concentration in thefiltrate is measured with HPLC or LC/MS/MS by the absolute calibrationmethod.

Test Example 4 Metabolism Stability Test

Using a commercially available pooled human hepatic microsomes, a testcompound was reacted for a constant time, a remaining rate wascalculated by comparing a reacted sample and an unreacted sample,thereby, a degree of metabolism in liver was assessed.

A reaction was performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 μL of the reaction solution was addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The test compound in the supernatant wasquantified by LC/MS/MS, and a remaining amount of the test compoundafter the reaction was calculated, letting a compound amount at 0 minutereaction time to be 100%. Hydrolysis reaction was performed in theabsence of NADPH and glucuronidation reaction was in the presence of 5mM UDP-glucuronic acid in place of NADPH, followed by similaroperations.

Test Example 5 hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation, effects on delayed rectifier K+ current (I_(Kr)), whichplays an important role in the ventricular repolarization process, wasstudied using HEK293 cells expressing human ether-a-go-go related gene(hERG) channel.

After a cell was retained at a membrane potential of −80 mV by wholecell patch clamp method using an automated patch clamp system(PatchXpress 7000A, Axon Instruments Inc.), I_(Kr) induced bydepolarization pulse stimulation at +40 mV for 2 seconds and, further,repolarization pulse stimulation at −50 mV for 2 seconds was recorded.After the generated current was stabilized, extracellular solution(NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH₂PO₄: 0.3 mmol/L, CaCl₂.2H₂O: 1.8mmol/L, MgCl₂.6H₂O: 1 mmol/L, glucose: 10 mmol/L, HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4)in which the test compound had been dissolved at an objectiveconcentration was applied to the cell under the room temperaturecondition for 10 minutes. From the recording I_(Kr), an absolute valueof the tail peak current was measured based on the current value at theresting membrane potential using an analysis software (DataXpress ver.1, Molecular Devices Corporation). Further, the % inhibition relative tothe tail peak current before application of the test substance wascalculated, and compared with the vehicle-applied group (0.1% dimethylsulfoxide solution) to assess influence of the test substance on I_(Kr).

Test Example 6 CPE Inhibitory Effect Confirming Assay <Material>

2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (MinimumEssential Medium) (Invitrogen))0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM (MinimumEssential Medium) (Invitrogen))

HBSS (Hanks' Balanced Salt Solution)

MDBK cell

Cells were adjusted to the appropriate cell number (3×10⁵/mL) with 2%FCS E-MEM.

MDCK Cell

After washing with HBSS two times, cells were adjusted to theappropriate cell number (5×10⁵/mL) with 0.5%

BSA E-MEM. Trypsin Solution

Trypsin from porcine pancreas (SIGMA) was dissolved in PBS(−), andfiltrated with a 0.45 μm filter.

EnVision (Perkin Elmer) WST-8 Kit (Kishida Chemical Co., Ltd.)

10% SDS solution

<Operation Procedure> Dilution and Dispensation of Test Sample

As a culture medium, 2% FCS E-MEM was used at the use of MDBK cells, and0.5% BSA E-MEM was used at the use of MDCK cells. Hereinafter, fordiluting virus, cells and a-test sample, the same culture medium wasused.

A test sample was diluted with a culture medium to a appropriateconcentration in advance, and then 2 to 5-fold serial dilution on a 96well plate (50 μL/well) was prepared. Two plate, one for measuringanti-Flu activity and the another for measuring cytotoxicity, wereprepared. Each assay was performed triplicate for each drug.

At the use of MDCK cells, trypsin was added to the cells to be a finalconcentration of 3 μg/mL only for measuring anti-Flu activity.

Dilution and Dispensation of Influenza Virus

An influenza virus was diluted with a culture medium to a appropriateconcentration in advance, and each 50 μL/well was dispensed on a 96-wellplate containing a test substance. Each 50 μL/well of a culture mediumwas dispensed on a plate containing a test substance for measuringcytotoxity.

Dilusion and Dispensation of Cell

Each 100 μL/well of cells which had been adjusted to the appropriatecell number was dispensed on a 96 well plate containing a testsubstance. This was mixed with a plate mixer, and incubated in a CO₂incubator for 3 days for measuring anti-Flu activity and measuringcytotoxity.

Dispensation of WST 8

The cells in 96-well plate which had been incubated for 3 days wasobserved visually under a microscope, and appearance of the cells, thepresence or absence of a crystal of test substance were checked. Thesupernatant was removed so that the cells were not absorbed from theplate.

WST-8 Kit was diluted 10-fold with a culture medium, and each 100 μL wasdispensed into each well. After mixing with a plate mixer, cells wereincubated in a CO₂ incubator for 1 to 3 hours.

After incubation, regarding the plate for measuring anti-Flu activity,each 10 L/well of a 10% SDS solution was dispensed in order toinactivate a virus.

Measurement of Absorbance

After the 96-well plate was mixed, absorbance was measured with EnVisionat two wavelengthes of 450 nm/620 nm.

<Calculation of Each Measurement Item Value>

The value was calculated using Microsoft Excel or a program having theequivalent calculation and processing ability, based on the followingcalculation equation. Calculation of effective concentration to achieve50% CPE inhibition (EC50)

EC50=10̂Z

Z=(50%−High %)/(High %−Low %)×{log(High conc.)−log(Low conc.)}+log(Highconc.)

IC₅₀ values of test substances are shown in Table 12-21.

TABLE 12 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 2 0.048 0.293 14 0.0430.313 16 0.065 0.632 26 0.108 0.547 37 0.101 0.318 43 0.078 1.410 480.087 10.90 56 0.358 3.860 62 0.110 1.680 63 0.170 2.000 94 0.096 1.47099 0.341 2.000 108 0.037 0.019 128 0.063 0.416 138 0.166 0.100 139 0.1890.741 143 0.224 0.333 150 0.193 0.553 175 0.132 0.102 178 0.061 0.075

TABLE 13 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 181 0.049 0.349 1820.099 0.562 183 0.074 2.370 184 0.055 0.403 185 0.132 1.920 186 0.0850.159 187 0.085 0.282 190 0.143 2.640 191 0.238 2.820 199 0.236 2.720204 0.299 2.360 224 0.276 0.119 225 0.283 0.663 228 0.243 0.141 2300.282 0.525 233 0.228 2.240 238 0.101 0.440 240 0.037 0.048 241 0.1970.063 242 0.114 0.059 243 0.076 0.020 244 0.249 0.108 246 0.082 0.026247 0.282 2.260 248 0.103 0.489 249 0.151 1.890 250 0.113 0.476 2510.058 0.157 252 0.107 0.454 253 0.235 0.280 254 0.135 0.564 255 0.0520.319 256 0.038 0.400

TABLE 14 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 257 0.041 0.055 2580.042 0.028 259 0.066 0.026 260 0.091 0.065 261 0.058 0.047 262 0.0320.038 263 0.085 0.075 264 0.064 0.128 265 0.172 0.036 266 0.043 0.085267 0.029 0.063 268 0.018 0.074 269 0.073 0.417 270 0.058 0.129 2710.073 0.102 272 0.082 0.030 273 0.016 0.084 274 0.038 0.016 274 0.1570.056 276 0.053 0.089 277 0.039 0.071 278 0.205 0.074 279 0.056 0.119280 0.068 0.145 281 0.026 0.018 282 0.036 0.029 283 0.028 0.021 2840.042 0.019 285 0.044 0.017 286 0.161 0.121 287 0.154 0.268 288 0.2990.085 289 0.031 0.419

TABLE 15 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 290 0.067 0.492 2920.155 2.230 293 0.290 0.437 294 0.035 0.018 295 0.052 0.334 296 0.1300.397 297 0.045 0.033 298 0.044 0.012 299 0.050 0.015 300 0.058 0.021301 0.062 0.017 302 0.035 0.014 304 0.018 0.015 305 0.059 0.103 3060.076 0.021 307 0.052 0.095 308 0.072 0.019 309 0.040 0.013 310 0.1080.522 311 0.040 0.026 312 0.019 0.029 313 0.189 0.050 314 0.149 0.026315 0.057 0.115 316 0.069 0.083 317 0.048 0.017 318 0.130 0.015 3200.045 0.011 321 0.019 0.019 322 0.113 0.028 323 0.077 0.019 324 0.1070.035 325 0.032 0.025

TABLE 16 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 326 0.043 0.005 3270.092 0.024 328 0.029 0.168 329 0.058 0.023 330 0.026 0.019 331 0.0450.335 332 0.048 0.020 333 0.021 0.425 334 0.075 0.032 335 0.019 0.016336 0.051 0.070 337 0.058 0.028 338 0.074 0.085 339 0.183 0.040 3400.101 0.027 341 0.016 0.027 342 0.099 0.026 343 0.122 0.018 344 0.0500.009 345 0.097 0.008 346 0.028 0.018 347 0.014 0.017 348 0.054 0.080349 0.053 0.075 351 0.091 0.019 352 0.067 0.020 354 0.025 0.083 3550.040 0.075 356 0.066 0.020 357 0.138 0.386 358 0.051 0.069 359 0.0370.080 360 0.042 0.087

TABLE 17 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 361 0.039 0.145 3620.084 0.067 363 0.058 0.067 364 0.112 0.515 365 0.041 2.250 366 0.0900.838 368 0.140 0.470 369 0.294 0.434 370 0.113 0.061 371 0.161 0.074372 0.164 0.146 373 0.065 0.050 374 0.137 0.154 375 0.037 0.073 3760.063 0.092 377 0.024 0.022 378 0.047 0.022 380 0.123 0.018 381 0.2000.034 382 0.032 0.094 384 0.153 0.293 386 0.075 0.096 387 0.300 1.150388 0.133 0.063 390 0.095 0.029 391 0.264 0.071 392 0.153 0.025 3940.087 0.064 395 0.043 0.089 396 0.056 0.060 397 0.055 0.077 398 0.0340.118 399 0.105 0.061

TABLE 18 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 400 0.067 0.079 4010.089 0.133 402 0.085 0.081 403 0.090 0.070 404 0.084 0.063 405 0.0740.051 406 0.119 0.022 407 0.035 0.017 408 0.135 0.061 409 0.093 0.029410 0.265 0.014 411 0.046 0.014 412 0.292 0.203 413 0.050 0.005 4141.890 0.131 415 0.285 0.022 416 0.112 0.019 417 0.030 0.003 418 0.1210.072 419 0.124 0.019 420 0.058 0.021 423 0.280 0.019 425 0.183 0.047429 0.016 0.004 430 0.168 0.029 431 0.097 0.011 432 0.155 0.062 4330.014 0.017 441 0.044 0.005 443 0.166 0.004 444 0.066 0.003 445 0.0130.004 446 0.007 0.011

TABLE 19 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 447 0.096 0.018 4480.039 0.008 449 0.062 0.021 450 0.023 0.014 452 0.177 0.016 453 0.1860.049 454 0.012 0.004 455 0.025 0.071 456 0.032 0.004 457 0.242 0.014458 0.048 0.014 459 0.287 0.048 460 0.085 0.009 461 0.255 0.074 4620.069 0.011 463 0.012 0.005 464 0.024 0.014 469 0.016 0.004 470 0.0080.003 475 0.164 0.441 476 0.031 0.014 478 0.088 0.129 479 0.117 0.064480 0.151 0.084 481 0.114 0.086 482 0.103 0.031 483 0.101 0.027 4850.221 0.424 486 0.140 0.072 487 0.091 0.026 488 0.151 0.027 489 0.1330.014 490 0.212 0.468

TABLE 20 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 491 0.069 0.099 4920.121 0.160 493 0.112 0.101 495 0.277 0.310 496 0.170 0.177 497 0.2150.511 498 0.161 0.351 502 0.042 0.142 506 0.247 1.620 507 0.063 0.197508 0.036 0.056 509 0.015 0.014 511 0.175 0.015 514 0.049 0.018 5150.197 0.019 516 0.039 0.017 518 0.049 0.024 520 0.212 0.017 521 0.1910.015 522 0.039 0.014 523 0.035 0.014 524 0.057 0.026 525 0.141 0.090526 0.044 0.019 527 0.127 0.088 532 0.098 0.075 533 0.065 0.391 5340.165 1.200 536 0.071 0.027 537 0.152 0.022 538 0.196 0.030 544 0.1680.051 546 0.202 0.124

TABLE 21 CEN IC₅₀ CPE EC₅₀ Example No. (μM) (μM) 547 0.032 0.027 5480.086 0.038 549 0.076 2.100 550 0.042 0.042 551 0.041 0.107 552 0.2300.085 553 0.028 0.030 554 0.065 0.465 555 0.023 0.012 556 0.023 0.412557 0.281 2.470 558 0.114 0.541 560 0.027 0.173 561 0.073 0.008 5620.022 0.062 563 0.049 0.464 564 0.088 0.136 565 0.154 0.726 568 0.2642.810 569 0.138 1.010 570 0.081 2.050 571 0.065 0.320 573 0.055 0.158574 0.165 0.442 575 0.058 0.087 576 0.063 0.027 577 0.233 0.337 5810.083 0.480

Test Example 7 Influenza Virus-Infected Mouse Lethality Inhibitory Test<Mouse>

BALB/cAnNCrlCrlj (female, 5-week-old; CHARLES RIVER LABORATORIES JAPAN,INC.) was purchased, and 6- to 7-week-old mice were used in the test.

<Preparation of Virus Solution>

A/Victoria/3/75 or B/Maryland/l/59 (ATCC) was passaged in mouse lung tomake a mouse-acclimatized virus. A freezing-stored mouse-acclimatizedvirus solution was rapidly thawed, and diluted with DPBS to aninfectivity titer to be used (in the case of A/Victoria/3/75:750TCID₅₀/mouse, in the case of B/Maryland/l/59:100 TCID₅₀/mouse).

<Infection>

Under anesthesia with ketamine*xylazine, 100 ul of the prepared virussolution was nasally inoculated to directly infect mouse lung.

<Preparation of Test Sample>

A test sample was dissolved in a 5% DMAA/20% HP-β-CD aqueous solution toa suitable concentration.

<Administration of Test Sample to Infected Mouse>

A suitably diluted test sample was intravenously administered at 200 ulto a mouse immediately after virus infection, by a single dose.

<Drug Efficacy Assessment>

The mouse was reared for 14 days after virus infection, and a necessarydose per day for 50% lethality inhibition, ED₅₀ (mg/kg/day), a lethalityinhibition rate at a maximum dose (% survival), or days during which themouse survives 50% as compared with a control at a maximum dose (50%life extension days) was calculated.

<Euthanasia>

The mouse after completion of the test was euthanized by carbon dioxideor halothane excessive administration.

The present compound exhibits the effect of inhibiting lethality of aninfluenza virus-infected mouse in the above test. Therefore, the presentcompound is effective in treating and/or preventing an influenzainfectious disease.

Formulation Example 1

A granule containing the following ingredients is manufactured.

Ingredient A compound shown by formula (I)  10 mg lactose 700 mgcornstarch 274 mg HPC-L  16 mg 1000 mg 

A compound shown by formula (I) and lactose are passed through a 60 meshsieve. Corn starch is passed through a 120 mesh sieve. These are mixedwith V-type blender. To the mixture, aqueous HPC-L (low viscosity ofhydroxypropylcellulose) is added, then the mixture is kneaded together,granulated (extrusive granulation pore diameter 0.5˜1 mm), and dried.The obtained dried granule is passed through vibrating sieve (12/60mesh) to obtain a granule.

Formulation Example 2

A granule for encapsulation containing the following ingredients ismanufactured.

Ingredient A compound shown by formula (I) 15 mg lactose 90 mgcornstarch 42 mg HPC-L  3 mg 150 mg 

A compound shown by formula (I) and lactose are passed through a 60 meshsieve. Corn starch is passed through a 120 mesh sieve. These are mixedand aqueous HPC-L (low viscosity of hydroxypropylcellulose) is addedthereto, then the mixture is kneaded together, granulated, and dried.The obtained dried granule is trimmed and 150 mg thereof is filled intoa No. 4 hard gelatin capsule.

Formulation Example 3

A tablet containing the following ingredients is manufactured.

Ingredient A compound shown by formula (I) 10 mg lactose 90 mgmicrocrystal cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg 150mg 

A compound shown by formula (I), lactose, and microcrystal cellulose,CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 meshsieve and mixed. Magnesium stearate is added to the mixed powder toobtain a mixture for tablet. The mixture is tabletted directly to obtaina 150 mg tablet.

Formulation Example 4

An injectable solution is manufactured by mixing the followingingredients under warming, followed by sterilization.

Ingredient A compound shown by formula (I)  3 mg non-ion surfactant 15mg  Water for injection 1 ml

INDUSTRIAL APPLICABILITY

The compound of the present invention has cap-dependent endonuclease(CEN) inhibitory activity. The compound of the present invention can bea useful agent for treatment and/or prevention of symptom and/or diseaseinduced by infection with influenza virus.

1-35. (canceled)
 36. A compound represented by formula (II), or apharmaceutically acceptable salt thereof or a solvate thereof:

(wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C, —Z—N(R^(A1))(R^(A2)), —Z—N(R^(A3))—SO₂—(R^(A4)),—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)), —Z—N(R^(A7))—C(═O)—R^(A8), —Z—S—R^(A9),—Z—SO₂—R^(A10), —Z—S(═O)—R^(A11), —Z—N(R^(A12))—C(═O)—O—R^(A13),—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21) (wherein R^(A1), R^(A2), R^(A3),R^(A5), R^(A7), R^(A8), R^(A9), R^(A12), R^(A13), R^(A14), R^(A15),R^(A16), R^(A17), R^(A1), R^(A19), R^(A20), and R^(A21) are eachindependently selected from a substituent group consisting of hydrogen,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C, R^(A4), R^(A6), R^(A10),and R^(A11) are each independently selected from a substituent groupconsisting of, lower alkyl optionally substituted by substituent groupC, lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C, R^(A1) and R^(A2),R^(A15) and R^(A16), and R^(A18) and R^(A19) each may be taken togetherwith an adjacent atom to form heterocyce, and Z is a bond or straight orbranched lower alkylene); R^(2a) is hydrogen, halogen, hydroxy, carboxy,cyano, formyl, lower alkyl optionally substituted by substituent groupC, lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, lower alkyloxyoptionally substituted by substituent group C, lower alkenyloxyoptionally substituted by substituent group C, lower alkylcarbonyloptionally substituted by substituent group C, lower alkyloxycarbonyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxy optionallysubstituted by substituent group C, carbocycleoxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, heterocycle lower alkyl optionallysubstituted by substituent group C, heterocyclecarbonyl optionallysubstituted by substituent group C, heterocycleoxy optionallysubstituted by substituent group C, heterocycleoxycarbonyl optionallysubstituted by substituent group C, —Z—N(R^(B1))—SO₂—R^(B2),—Z—N(R^(B3))—C(═O)—R^(B4), —Z—N(R^(B5))—C(═O)—O—R^(B6),—Z—C(═O)—N(R^(B7))(R^(B8)), —Z—N(R^(B9))(R^(B10)), or —Z—SO₂—R^(B11)(wherein R^(B1), R^(B3), R^(B4), R^(B5), R^(B6), R^(B7), R^(B8), R^(B9),and R^(B10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC, R^(B2) and R^(B11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C, R^(B7) and R^(B8),and R^(B9) and R^(B10) each may be taken together with an adjacent atomto form heterocycle, and Z is a bond or straight or branched loweralkylene); R³ is hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C, —Z—N(R^(C1))—SO₂—R^(C2), —Z—N(R^(C3))—C(═O)—R^(C4),—Z—N(R^(C5))—C(═O)—O—R^(C6), —Z—C(═O)—N(R^(C7))(R^(C8)),—Z—N(R^(C9))(R^(C10)), —Z—SO₂—R^(C11), or —Z—N(R^(C12))—O—C(═O)—R^(C13)(wherein R^(C1), R^(C3), R^(C4), R^(C5), R^(C6), R^(C7), R^(C8), R^(C9),R^(C10), R^(C12) and, R^(C13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C, R^(C2) and R^(C11) are each independentlyselected from a substituent group consisting of lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C, R^(C7) and R^(C8), and R^(C9) and R^(C10) eachmay be taken together with an adjacent atom to form heterocycle, and Zis a bond or straight or branched lower alkylene) and; B¹ is NR^(7a) andB² is CR^(5a)R^(6a), R^(3a) and R^(6a) are taken together with anadjacent atom to form heterocycle optionally substituted by substituentgroup D, R^(5a) and R^(7a) are each independently selected from asubstituent group consisting of hydrogen, carboxy, cyano, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, lower alkyl carbonyl optionally substituted bysubstituent group C, lower alkyl oxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C, —Y—S—R^(D1), —Z—S(═O)—R^(D2), —Z—SO₂—R^(D3),—C(═O)—C(═O)—R^(D4), —C(═O)—N(R^(D5))(R^(D6)),—Z—C(R^(D7))(R^(D8))(R^(D9)), —Z—CH₂—R^(D10),—Z—N(R^(D11))—C(═O)—O—R^(D12), or —Z—N(R^(D13))—C(═O)—R^(D14) (whereinR^(D1), R^(D4), R^(D6), R^(D9), R^(D11), R^(D12), R^(D13), and R^(D14)are each independently selected from a substituent group consisting ofhydrogen, lower alkyl optionally substituted by substituent group C,lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C, R^(D2), and R^(D3)are each independently selected from a substituent group consisting oflower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C, R^(D7), R^(D8), andR^(D10) are each independently selected from a substituent groupconsisting of carbocyclic group optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, R^(D5) and R^(D6) may be taken together with an adjacent atom to formheterocycle, Y is straight or branched lower alkylene, and Z is a bondor straight or branched lower alkylene); R^(D5) and R^(D6) may be takentogether with an adjacent atom to form carbocycle; Substituent group C:halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, loweralkyl, halogeno lower alkyl, lower alkyloxy, lower alkylthio, hydroxylower alkyl, carbocyclic group, heterocyclic group, heterocyclic groupsubstituted by oxo, carbocycle lower alkyloxy, carbocycleoxy loweralkyl, carbocycle lower alkyloxy lower alkyl, heterocycle loweralkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy loweralkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, loweralkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino,halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, loweralkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino;Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno loweralkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy,lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, loweralkylsulfonylamino, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C).
 37. The compound according to claim 36, or thepharmaceutically acceptable salt thereof or the solvate thereof, whereinR^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C, —Z—N(R^(A1))(R^(A2)), —Z—N(R^(A3))—SO₂—(R^(A4)),—Z—N(R^(A7))—C(═O)—R^(A8), —Z—S—R^(A9), —Z—SO₂—R^(A10),—Z—N(R^(A12))—C(═O)—O—R^(A13), or —Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)(substituent group C, R^(A1), R^(A2), R^(A3), R^(A4), R^(A7), R^(A8),R^(A9), R^(A10), R^(A12), R^(A13), R^(A20), R^(A21), and Z are samemeaning as those of claim 36).
 38. The compound according to claim 36,or the pharmaceutically acceptable salt thereof or the solvate thereof,wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, —Z—N(R^(A1))(R^(A2)),—Z—N(R^(A7))—C(═O)—R^(A8), or —Z—N(R^(A12))—C(═O)—O—R^(A13) (substituentgroup C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13), and Z aresame as those of claim 36).
 39. The compound according to claim 36, orthe pharmaceutically acceptable salt thereof or the solvate thereof,wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, or —Z—N(R^(A1))(R^(A2)) (substituentgroup C, R^(A1), R^(A2), and Z are same as those of claim 36).
 40. Thecompound according to claim 36, or the pharmaceutically acceptable saltthereof or the solvate thereof, wherein R^(1a) is hydrogen, or carboxy.41. The compound according to claim 36, or the pharmaceuticallyacceptable salt thereof or the solvate thereof, wherein R^(2a) ishydrogen, lower alkyl optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or —Z—N(R^(B9))(R^(B10)) (substituent group C, R^(B9), R^(B10), and Zare same as those of claim 36).
 42. The compound according to claim 36,or the pharmaceutically acceptable salt thereof or the solvate thereof,wherein R^(2a) is hydrogen or lower alkyl optionally substituted bysubstituent group C (substituent group C is same as that of claim 36).43. The compound according to claim 36, or the pharmaceuticallyacceptable salt thereof or the solvate thereof, wherein the formula (II)is the formula (II″) represented by

wherein ring is a 5- to 7-membered heterocycle ring (R^(1a), R^(2a),R^(5a), R^(7a) and R^(A12) are same as those of claim 36).
 44. Thecompound according to claim 43, or the pharmaceutically acceptable saltthereof or the solvate thereof, wherein R^(7a) is the following groups:

wherein R^(E6) is selected from a substituent group C, m is an integerof 0 or more.
 45. The compound according to claim 36, or thepharmaceutically acceptable salt thereof or the solvate thereof, whereinsubstituent group D is carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C (wherein substituent group C is same as that ofclaim 36).
 46. A pharmaceutical composition containing a compoundaccording to claim 36, or a pharmaceutically acceptable salt thereof ora solvate thereof.
 47. The pharmaceutical composition according to claim46 which exhibits anti influenza activity.
 48. A method for treatingand/or preventing influenza infectious disease, the method comprisingadministering the compound according to claim 36 or the pharmaceuticallyacceptable salt thereof or the solvate thereof.